CN103998450B - Pyrrolobenzodiazepines are tall and erect - Google Patents

Pyrrolobenzodiazepines are tall and erect Download PDF

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Publication number
CN103998450B
CN103998450B CN201280062290.1A CN201280062290A CN103998450B CN 103998450 B CN103998450 B CN 103998450B CN 201280062290 A CN201280062290 A CN 201280062290A CN 103998450 B CN103998450 B CN 103998450B
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alkyl
junction point
methyl
compound
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CN103998450A (en
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菲利普·威尔逊·霍华德
阿诺·蒂贝尔吉恩
斯科特·杰弗里
帕特里克·伯克
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MedImmune Ltd
Seagen Inc
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ADC Therapeutics SA
Seattle Genetics Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D519/00Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549Sugars, nucleosides, nucleotides or nucleic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/06Immunosuppressants, e.g. drugs for graft rejection
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20Carbocyclic rings
    • C07H15/22Cyclohexane rings, substituted by nitrogen atoms

Abstract

One kind has the compound of formula (I), wherein:R2For formula (II), wherein X is selected from OH, SH, CO2H, COH, N=C=O, NHNH2、CONHNH2, formula (A), formula (B), NHRNThe group of composition, wherein RNIt is selected from and include H and C1‑4The group of alkyl;RC1、RC2And RC3Independently selected from H and unsubstituted C1‑2Alkyl;And or:R12Selected from group consisting of:(ia)C5‑10Aryl, optionally substituted by one or more substituent groups, substituent group is selected from and includes following group:Halogen, nitro, cyano group, ether, C1‑7Alkyl, C3‑7Heterocyclic radical and dioxygen base C1‑3Alkylidene;(ib)C1‑5Radical of saturated aliphatic alkyl;(ic)C3‑6Saturated cyclic alkyls;(id) formula (C), wherein R21、R22And R23It is each independently selected from H, C1‑3Saturated alkyl, C2‑3Alkenyl, C2‑3Alkynyl and cyclopropyl, wherein in R12In group, the sum of carbon atom is not more than 5;(ie) formula (D), wherein R25aAnd R25bOne of be H and another is selected from phenyl, this phenyl is optionally substituted by the group selected from halogen, methyl, methoxyl group;Pyridine radicals;And thiophenyl;And (if) formula (E), wherein R24It is selected from:H;C1‑3Saturated alkyl;C2‑3Alkenyl;C2‑3Alkynyl;Cyclopropyl;Phenyl, this phenyl is optionally substituted by the group selected from halogen, methyl, methoxyl group;Pyridine radicals;And thiophenyl;R6And R9Independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR ', nitro, Me3Sn and halogen;Wherein R and R ' is independently selected from optionally substituted C1‑12Alkyl, C3‑20Heterocyclic radical and C5‑20Aryl;R7Selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR ', nitro, Me3Sn and halogen;Or:(a)R10It is H, and R11It is OH, ORA, wherein RAIt is C1‑4Alkyl;(b)R10And R11Form nitrogen carbon double bond between the nitrogen that they are combined and carbon atom;Or (c) R10It is H and R11It is SOzM, wherein z are 2 or 3 and M to be univalent medicinal cation;R " is C3‑12Alkylidene, this chain can be by one or more hetero atoms, and/or aromatic ring is interrupted;Y and Y ' is selected from O, S or NH;R6’、R7’、R9’It is respectively selected from and R6、R7And R9Identical group, and R10’And R11’With R10And R11Identical, if wherein R11And R11’It is SOzM, then M can represent bivalence medicinal cation

Description

Pyrrolobenzodiazepines are tall and erect
Technical field
The present invention relates to Pyrrolobenzodiazepines(Pyrrolobenzodiazepines are tall and erect, PBD), particularly pyrrolo- benzo DiazaDimer, this dimer has a monomeric unit, and it has C2-C3 double bond and the aryl at C2 position, and Second comonomer unit, it has C2-C3 double bond and the substituted propylidene at C2 position, and they include combining in target In thing (conjugate).
Background technology
Some Pyrrolobenzodiazepines(PBD) it is capable of identify that and is incorporated into the particular sequence of DNA;Preferably sequence is PuGPu.Find PBD antitumor antibiotics, antramycin (anthramycin) (Leimgruber, et in nineteen sixty-five al.,J.Am.Chem.Soc.,87,5793-5795(1965);Leimgruber,et al.,J.Am.Chem.Soc.,87, 5791-5793(1965)).Thereafter, report the PBD of many naturally occurrings, and develop many conjunctions for various analogs One-tenth approach (Thurston, et al., Chem.Rev.1994,433-465 (1994);Antonow,D.and Thurston, D.E.,Chem.Rev.2011111(4),2815-2864).Family member include abbeymycin (Hochlowski, et al., J.Antibiotics, 40,145-148 (1987)), strange Ka-7038Ⅶ (chicamycin) (Konishi, et al., J.Antibiotics, 37,200-206 (1984)), DC-81 (Japan Patent 58-180487;Thurston,et al., Chem.Brit.,26,767-772(1990);Bose, et al., Tetrahedron, 48,751-758 (1992)), methyl ammonia Anthramycin (mazethramycin) (Kuminoto, et al., J.Antibiotics, 33,665-667 (1980)), Xin Sila Mycin (neothramycin) A and B (Takeuchi, et al., J.Antibiotics, 29,93-96 (1976)), porothramycin(Tsunakawa,et al.,J.Antibiotics,41,1366-1373(1988))、 prothracarcin(Shimizu,et al,J.Antibiotics,29,2492-2503(1982);Langley and Thurston, J.Org.Chem., 52,91-97 (1987)), sibanomicin (sibanomicin) (DC-102) (Hara, et al.,J.Antibiotics,41,702-704(1988);Itoh,et al.,J.Antibiotics,41,1281-1284 (1988)), sibiromycin (sibiromycin) (Leber, et al., J.Am.Chem.Soc., 110,2992-2993 ) and tomamycin (tomamycin) (Arima, et al., J.Antibiotics, 25,437-444 (1972)) (1988).PBD For following general structure:
Their difference is quantity, type and the position of substituent group, is their aromatics A ring and pyrrolo- C ring two Person, and it is C ring filling degree.In B ring, at N10-C11 position (it is responsible for making the alkylating electrophilic center of DNA) place There is imines (N=C), carbinolamine (carbinolamine) (NH-CH (OH)) or carbinolamine methyl ether (NH-CH (OMe)).All Known natural product has (S)-configuration at chiral C11a position, and when observing from C ring to A ring, this configuration carries to them Reverse (right-handed twist) for the right hand.This give they for the ditch of B-form DNA etc. helicity (isohelicity) suitable 3D shape, obtains (Kohn, the In Antibiotics that is slidably matched at binding site III.Springer-Verlag,New York,pp.3-11(1975);Hurley and Needham-VanDevanter, Acc.Chem.Res.,19,230-237(1986)).The ability that they form adduct in ditch allows them to disturb DNA processes, and therefore they can be used as antitumor agent.
Previously disclosed can will be mono- for two PBD by their C8/C '-hydroxy functional group via flexible alkylene linker Unit be joined together to strengthen these molecules biological activity (Bose, D.S., et al., J.Am.Chem.Soc., 114, 4939-4941(1992);Thurston,D.E.,et al.,J.Org.Chem.,61,8141-8147(1996)).PBD dimerization Body is considered as forming 5 '-Pu-GATC-Py-3 ' interchain linkage (Smellie, M., the et of the sequence selective DNA damage such as palindrome al.,Biochemistry,42,8232-8239(2003);Martin,C.,et al.,Biochemistry,44,4135- 4147), it is considered mainly to be responsible for their biological activity.The dimeric example of PBD, SG2000 (SJG-136):
Have been enter into recently II clinical trial phase in oncology (Gregson, S., et al., J.Med.Chem., 44,737-748(2001);Alley,M.C.,et al.,Cancer Research,64,6700-6706(2004); Hartley,J.A.,et al.,Cancer Research,64,6693-6699(2004)).
Recently, in WO2005/085251, the present inventor previously disclosed the dimer with C2 aryl substituent PBD compound, such as SG2202 (ZC-207):
And in WO2006/111759, disclose the bisulfites of above-mentioned PBD compound, such as SG2285 (ZC- 423):
Have shown these compounds be highly useful cytotoxic agent (Howard, P.W., et al., Bioorg.Med.Chem.(2009),19(22),6463-6466,doi:10.1016/j.bmcl.2009.09.012).
Due to these model of action in crosslinked DNA for the highly effective compound, these molecules are prepared to symmetry. This provides direct synthesis:By building the PBD part with established dimer key simultaneously, or by making to have been built up PBD part react with dimer linking group.
WO2010/043880 discloses asymmetrical dimer PBD compound, and it carries at the C2 position of each monomer Aryl, wherein one of these aryl carry substituent group, and it is designed to provide for connecting compound to another part Deadman.International Application Serial No. PCT/the US2011/032664 (on April 15th, 2011 submission) of CO-PENDING, is disclosed as WO2011/ 130613, disclose and include these PBD dimer compounds in target conjugate.The International Application Serial No. PCT of CO-PENDING/ US2011/032668 (on April 15th, 2011 submission), is disclosed as WO2011/130616, discloses asymmetrical dimer PBD Compound, this compound carries aryl at the C2 position of a monomer, and above-mentioned monomer carries substituent group, and it is designed to carry For for connecting compound to the deadman of another part, another monomer carries nonaromatic at C2 position.Also public Open and included these compounds in target conjugate.
Content of the invention
The present inventor further developed asymmetrical dimer PBD compound, is used for including in target conjugate, Thus the aryl of deadman need not be carried.In the present invention, with being designed to provide for connecting compound to another The C2 group of the substituent group of partial deadman is propylidene.These compounds can easily synthesize have in the following areas excellent Point:The biological nature of their application, particularly their biological nature and the synthesis of conjugate and these conjugates.
The present invention includes the compound with Formulas I:
Or its pharmaceutical salts or solvate,
Wherein:
R2For Formula II:
Wherein X is selected from and includes following group:OH、SH、CO2H, COH, N=C=O, NHNH2、CONHNH2NHRN, wherein RNIt is selected from and include H and C1-4The group of alkyl;
RC1、RC2And RC3Independently selected from H and unsubstituted C1-2Alkyl;
And or:
R12Selected from group consisting of the following:
(ia)C5-10Aryl, is alternatively replaced by one or more substituent groups, and above-mentioned substituent group is selected from below inclusion Group:Halogen, nitro, cyano group, ether, C1-7Alkyl, C3-7Heterocyclic radical and double-epoxide-C1-3Alkylidene;
(ib)C1-5Radical of saturated aliphatic alkyl;
(ic)C3-6Saturated cyclic alkyls;
(id)Wherein R21、R22And R23It is each independently selected from H, C1-3Saturated alkyl, C2-3Alkenyl, C2-3Alkynyl and cyclopropyl, wherein in R12In group, the sum of carbon atom is not more than 5;
(ie)Wherein R25aAnd R25bOne of be H and another be selected from:(this phenyl is can to phenyl Selection of land by selected from halogen, methyl, methoxyl group substituent group);Pyridine radicals;And thiophenyl;And
(if)Wherein R24Selected from H;C1-3Saturated alkyl;C2-3Alkenyl;C2-3Alkynyl;Cyclopropyl;Phenyl (this phenyl be alternatively by selected from halogen, methyl, methoxyl group substituent group);Pyridine radicals;And thiophenyl;
R6And R9Independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR ', nitro, Me3Sn and halogen;
Wherein R and R ' is independently selected from optionally substituted C1-12Alkyl, C3-20Heterocyclic radical and C5-20Aryl;
R7Selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR ', nitro, Me3Sn and halogen;
Or:
(a)R10It is H, and R11It is OH, ORA, wherein RAIt is C1-4Alkyl;Or
(b)R10And R11Form nitrogen-carbon double bond between the nitrogen that they are combined and carbon atom;Or
(c)R10It is H and R11It is SOzM, wherein z are 2 or 3 and M to be univalent medicinal cation;
R " is C3-12Alkylidene, this chain can be by one or more hetero atoms, such as O, S, NRN2(wherein RN2It is H or C1-4 Alkyl), and/or aromatic ring, such as benzene or pyridine are interrupted;
Y and Y ' is selected from O, S or NH;
R6’、R7’、R9’It is respectively selected from and R6、R7And R9Identical group and R10’And R11’With R10And R11Identical, wherein such as Fruit R11And R11’It is SOzM, then M can represent bivalence medicinal cation.
The compound that a second aspect of the present invention provides a first aspect of the present invention is used for treating Hypertrophic disease in preparation Application in the medicine of disease.Second aspect additionally provides the compound of a first aspect of the present invention in treatment proliferative disease Application.
Those of ordinary skill in the art can easily determine whether candidate's conjugate treats any particular cell types Proliferative disorders.For example, in the examples below, describe such mensure, it can be conveniently used for assessment by specialization The activity that compound provides.
A third aspect of the present invention includes the compound of Formula II:
Or its pharmaceutical salts or solvate,
Wherein:
R2There is Formula II:
Wherein X is selected from and includes following group:OH、SH、CO2H, COH, N=C=O, NHNH2、CONHNH2NHRN, wherein RNIt is selected from and include H and C1-4The group of alkyl, and or:
R12Selected from group consisting of:
(ia)C5-10Aryl, is alternatively replaced by selected from the one or more substituent groups including following group:Halogen, nitre Base, cyano group, ether, C1-7Alkyl, C3-7Heterocyclic radical and double-epoxide-C1-3Alkylidene;
(ib)C1-5Radical of saturated aliphatic alkyl;
(ic)C3-6Saturated cyclic alkyls;
(id)Wherein R21、R22And R23It is each independently selected from H, C1-3Saturated alkyl, C2-3Alkenyl, C2-3Alkynyl and cyclopropyl, wherein in R12In group, the sum of carbon atom is not more than 5;
(ie)Wherein R25aAnd R25bOne of be H and another is selected from:(this phenyl is by selecting to phenyl Optionally substituted from following group:Halogen, methyl, methoxyl group);Pyridine radicals;And thiophenyl;And
(if)Wherein R24It is selected from:H;C1-3Saturated alkylC2-3Alkenyl;C2-3Alkynyl;Cyclopropyl;Phenyl (this phenyl is by optionally substituted selected from following group:Halogen, methyl, methoxyl group);Pyridine radicals;And thiophenyl;
R6And R9Independently selected from H, R, OH, OR, SH, SR.NH2, NHR, NRR ', nitro, Me3Sn and halogen;
Wherein R and R ' is independently selected from optionally substituted C1-12Alkyl, C3-20Heterocyclic radical and C5-20Aryl;
R7Selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR ', nitro, Me3Sn and halogen;
Or:
(a)R10It is carbamate nitrogen-protecting group group, and R11It is O-ProtO, wherein ProtOIt is oxygen blocking group;Or
(b)R10It is hemiacetal amine nitrogen blocking group and R11It is epoxide;
R " is C3-12Alkylidene, this chain can be by one or more hetero atoms, such as O, S, NRN2(wherein RN2It is H or C1-4 Alkyl), and/or aromatic ring, such as benzene or pyridine are interrupted;
Y and Y ' is selected from O, S or NH;
R6’、R7’、R9’It is respectively selected from and R6、R7And R9Identical group, and R10’And R11’With R10And R11Identical.
A fourth aspect of the present invention includes, by the deprotection of imine linkage from the compound or pharmaceutically acceptable salt thereof of Formula II or solvent Compound is preparing the compound or pharmaceutically acceptable salt thereof of Formulas I or the method for solvate.
By with preparing this from those the tactful different strategies being previously used for preparing symmetrical dimer PBD compound The asymmetrical dimer PBD compound of invention.Particularly, the present inventor has been developed for a kind of method, and it is related to single Each C2 substituent group is added symmetrical PBD dimer core by method and step.Therefore, a fifth aspect of the present invention provide for The method of the compound of first or the third aspect of the preparation present invention, including at least one of the method and step being set forth below.
At the 6th aspect, the present invention relates to conjugate, it comprises to be connected to the dimer of the PBD of targeting agent, wherein PBD bis- Aggressiveness is Formulas I or its pharmaceutical salts or solvate (seeing above).
In some embodiments, conjugate has following formula III:
L-(LU-D)p(III)
Or its pharmaceutical salts or solvate, wherein L is part unit (that is, targeting agent), and LU is connector unit and D is medicine Unit, it is PBD dimer (seeing below).Subscript p is 1 to 20 integer.Therefore, conjugate comprise covalent by connector unit It is connected to the part unit of at least one drug unit.Part unit (being described in more below) is targeting agent, and it is incorporated into Target part.Part unit is permissible, for example, is specifically incorporated into cell component (cell binding agent) or other target target molecules. Therefore, present invention also offers for treatment for example, the method for various cancers and autoimmune disease.These methods include using it Middle part unit is the conjugate of the targeting agent being specifically incorporated into target molecule.Part unit can be, for example, protein, Polypeptide or peptide, such as antibody, the Fab of antibody or other bonding agent, such as Fc fusion protein.
In the conjugate of the present invention, PBD dimer D is Formulas I or its pharmaceutical salts or solvate, and difference is X Choosing includes following group:*-O-+、*-S-+、*-CO2-+、*-CO-+, *-NH (C=O)-+、*-NHNH-+、*-CONHNH-+ Wherein RNIt is selected from and include H and C1-4The group of alkyl, asterisk Represent with the junction point of remainder of drug unit and wavy line or+Represent the junction point with connector unit.
To represent drug loading (drug load, drug with p (number of drug molecule/part unit (for example, antibody)) loading).Drug loading can be 1 to 20 drug unit (D)/part unit (for example, Ab or mAb).For compositionss, p table Show the drug loading of conjugate in the composition, and p scope is 1 to 20.
In some embodiments, p is about 1 to about 8 drug unit/part unit.In some embodiments, p is 1.In some embodiments, p is 2.In some embodiments, p is about 2 to about 8 drug unit/part units.One In a little embodiments, p is about 2 to about 6,2 to about 5 or 2 to about 4 drug unit/part units.In some embodiments In, p is about 2, about 4, about 6 or about 8 drug unit/part units.
Can be by conventional methods as mass spectrography, ELISA mensure and HPLC to be characterized in the preparation of association reaction The average number of drug unit/part unit.It may also be determined that the quantitative distribution of the conjugate being represented with p.In some cases, Homogeneous combination (wherein p is certain value) can be realized and there is other drug loading by way of such as reversed-phase HPLC or electrophoresis The separation of conjugate, purification and sign.
At the 7th aspect, the present invention relates to comprising to be connected to the joint-medicine of the dimer (seeing above) of the PBD of connector unit Compounds (that is, agent-linker).These agent-linker can serve as, for synthesizing the intermediate of conjugate, this conjugate Comprise the dimer being connected to targeting agent PBD.
These agent-linker have following Formula V:
LU-D (V)
Or its pharmaceutical salts or solvate, wherein LU is connector unit and D is drug unit, and it is PBD dimer.
In the agent-linker of the present invention, PBD dimer D is Formulas I or its pharmaceutical salts or solvate, difference It is, X is selected from and includes following group:*-O-q、*-S-q、*-CO2-q、*-CO-q, *-NH (C=O)-q、*-NHNH-q、*- CONHNH-q Wherein RNIt is selected from and include H and C1-4Alkyl Group, asterisk represent junction point with the remainder of drug unit and wavy line orqRepresent the junction point with connector unit.
Definition
Medicinal cation
The example of medicinal unit price and bivalent cation is discussed at Berge, et al., J.Pharm.Sci., 66,1-19 (1977), it is incorporated herein by reference.
Medicinal cation can be inorganic cation or organic cation.
The example of medicinal monovalent inorganic cation includes but is not limited to alkali metal ion such as Na+And K+.Medicinal divalent inorganic sun The example of ion includes but is not limited to alkaline earth metal cation such as Ca2+And Mg2+.The example of medicinal organic cation include but not It is limited to ammonium ion (i.e. NH4 +) and replace ammonium ion (such as NH3R+、NH2R2 +、NHR3 +、NR4 +).Some substituted ammoniums being suitable for The example of ion is derived from the ammonium ion that following those replace:Ethamine, diethylamine, hexanamine, triethylamine, butylamine, second two Amine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and trometamol and aminoacid, such as rely ammonia Acid and arginine.The example of common quaternary ammonium ion is N (CH3)4 +.
Substituent group
As used in this article, phrase " optionally substituted " be related to its can be unsubstituted or its can be replace Female group.
Unless otherwise prescribed, as used in this article, term " replacement " is related to it and carries one or more substituent groups Female group.Term " substituent group " be herein defined as in a conventional sense using and refer to such chemical part, it is covalent It is connected to, or if appropriate, condense in female group.Various substituent groups is it is well known that and being used for them The method forming and being introduced to various female groups is also well-known.
It is described in more detail below the example of substituent group.
C1-12Alkyl:As used in this article, term " C1-12Alkyl " is related to by from having 1 to 12 carbon atom The carbon atom of hydrocarbon compound remove the monovalent moiety that obtained of hydrogen atom, it can be aliphatic or alicyclic, and it is permissible It is saturation or undersaturated (for example partly undersaturated, completely undersaturated).As used in this article, term " C1-4Alkane Base " is related to by removing, from the carbon atom of the hydrocarbon compound with 1 to 4 carbon atom, the monovalent moiety that hydrogen atom is obtained, its Can be aliphatic or alicyclic, and it can be saturation or undersaturated (for example partly undersaturated, completely undersaturated). Therefore, the subclass that term " alkyl " inclusion is discussed below:Alkenyl, alkynyl, cycloalkyl etc..
The example of saturated alkyl includes but is not limited to methyl (C1), ethyl (C2), propyl group (C3), butyl (C4), amyl group (C5)、 Hexyl (C6) and heptyl (C7).
The example of saturated linear alkyl includes but is not limited to methyl (C1), ethyl (C2), n-pro-pyl (C3), normal-butyl (C4)、 N-pentyl (amyl group) (C5), n-hexyl (C6) and n-heptyl (C7).
The example of saturation branched alkyl includes isopropyl (C3), isobutyl group (C4), sec-butyl (C4), the tert-butyl group (C4), isoamyl Base (C5) and neopentyl (C5).
C2-12Alkenyl:As used in this article, term " C2-12Alkenyl " is related to there is one or more carbon-to-carbons The alkyl of double bond.
The example of unsaturated chain thiazolinyl includes but is not limited to vinyl (ethenyl) (vinyl, vinyl ,-CH=CH2)、 1- acrylic (- CH=CH-CH3), 2- acrylic (pi-allyl ,-CH-CH=CH2), isopropenyl (1- methyl ethylene ,-C (CH3)=CH2), cyclobutenyl (C4), pentenyl (C5) and hexenyl (C6).
C2-12Alkynyl:As used in this article, term " C2-12Alkynyl " is related to there is one or more carbon-to-carbon triple bonds Alkyl.
The example of unsaturated alkynyl includes but is not limited to acetenyl (- C ≡ CH) and 2-propynyl (2-propynyl) is (propargyl Base (propargyl) ,-CH2-C≡CH).
C3-12Cycloalkyl:As used in this article, term " C3-12Cycloalkyl " is related to be also the alkyl of ring group;That is, lead to Cross and remove, from the alicyclic ring atom of cyclic hydrocarbon (carbocyclic ring) compound, the monovalent moiety that hydrogen atom is obtained, this monovalent moiety has 3 to 7 Carbon atom, including 3 to 7 annular atoms.
The example of cycloalkyl includes but is not limited to those cycloalkyl, and it is derived from:
The monocyclic hydrocarbon compound of saturation;
Cyclopropane (C3), Tetramethylene. (C4), Pentamethylene. (C5), hexamethylene (C6), cycloheptane (C7), methyl cyclopropane (C4)、 Dimethylcyclopropane (C5), methyl cyclobutane (C5), dimethylcyclobutane (C6), methyl cyclopentane (C6), dimethylcyclopentane (C7) and hexahydrotoluene (C7);
Unsaturated monocyclic hydrocarbon compound;
Cyclopropylene (C3), cyclobutane (C4), cyclopentenes (C5), cyclohexene (C6), methyl cyclopropene (C4), dimethylcyclopropene (C5), methyl cyclobutane (C5), dimethyl cyclobutane (C6), methyl cyclopentene (C6), dimethylcyclopentene (C7) and methyl cyclohexane Alkene (C7);And
Saturation polycyclic hydrocarbon compounds:Norcarane (norcarane) (C7), norpinane (norpinane) (C7), norcamphane (fall Bornylane, norbornane) (C7).
C3-20Heterocyclic radical:As used in this article, term " C3-20Heterocyclic radical " is related to by the ring from heterocyclic compound Atom removes the monovalent moiety that hydrogen atom is obtained, and this part has 3 to 20 annular atoms, and wherein 1 to 10 is ring hetero atom. Preferably, each ring has 3 to 7 annular atoms, and wherein 1 to 4 is ring hetero atom.
In this context, prefix (such as C3-20、C3-7、C5-6, etc.) represent the number of annular atom or the number of annular atom Scope, but regardless of being carbon atom or hetero atom.For example, as used in this article, term " C5-6Heterocyclic radical " is related to be had The heterocyclic radical of 5 or 6 annular atoms.
The example of monocyclic heterocycles base is including but not limited to derived from those following monocyclic heterocycles bases:
N1:Aziridine (C3), azetidine (C4), pyrrolidine (nafoxidine) (C5), pyrrolin (for example, 3- pyrroles Quinoline, 2,5- pyrrolin) (C5), 2H- pyrroles or 3H- pyrroles's (different pyrroles, isoxazole) (C5), piperidines (C6), dihydropyridine (C6), tetrahydropyridine (C6), azepine(C7);
O1:Oxirane (oxirane) (C3), oxetanes (oxetane) (C4), tetrahydrofuran (tetrahydrochysene furan Mutter) (C5), oxole (divinylene oxide, oxole) (dihydrofuran) (C5), oxinane (exane) (Pentamethylene oxide .) (C6), dihydropyran (C6), pyrans (C6), oxa-(heptan, oxepin) (C7);
S1:Thiirane (C3), Thietane (C4), tiacyclopentane (Tetramethylene sulfide) (C5), thia hexamethylene (tetrahydric thiapyran) (C6), thia cycloheptane (thiepane) (C7);
O2:Dioxolane (C5), dioxane (C6) and Dioxepane (dioxepane) (C7);
O3:Trioxane (C6);
N2:Imidazolidine (C5), pyrazolidine (two azo alkane) (C5), imidazoline (C5), pyrazoline (pyrazoline) (C5), piperazine (C6);
N1O1:Tetrahydrochysene azoles (C5), dihydro azoles (C5), tetrahydrochysene isoxazole (C5), dihydro isoxazole (C5), morpholine (C6)、 Tetrahydrochysene piperazine (C6), dihydro piperazine (C6), piperazine (C6);
N1S1:Thiazoline (C5), Thiazolidine (C5), thiomorpholine (C6);
N2O1:Diazine (C6);
O1S1:Oxygen dithiole (thiophene, oxathiole) (C5) and thioxane (thiophene alkane) (C6);With And
N1O1S1:Thiazine (C6).
The example of the monocyclic heterocycles base replacing includes the monocyclic heterocycles base of those replacements, and it is derived from the saccharide of loop type, example As furanose (C5), such as arabinofuranosyl, lysol furanose (lyxofuranose), ribofuranose and furyl xylose , and pyranose (C (xylofuranse)6), such as other pyranose (allopyranose), pyrans altrose, Glucopyranose., Mannopyranose, pyrans gulose (gulopyranose), pyrans idose (idopyranose), galactopyranose and pyrans Talose (talopyranose).
C5-20Aryl:As used in this article, term " C5-20Aryl " is related to former by the aromatic ring from aromatic compounds Son removes the monovalent moiety that hydrogen atom is obtained, and it has 3 to 20 annular atoms.As used in this article, term " C5-7 Aryl " is related to by removing, from the aromatic ring atom of aromatic compounds, the monovalent moiety that hydrogen atom is obtained, and it has 5 to 7 rings Atom, and as used in this article, term " C5-10Aryl " is related to by removing from the aromatic ring atom of aromatic compounds The monovalent moiety that hydrogen atom is obtained, it has 5 to 10 annular atoms.Preferably, each ring has 5 to 7 annular atoms.
In this context, prefix (such as C3-20、C5-7、C5-6、C5-10Deng) represent annular atom (carbon atom or hetero atom) The scope of the number of number or annular atom.For example, as used in this article, term " C5-6Aryl " is related to there is 5 or 6 The aryl of annular atom.
Annular atom can be all carbon atom, such as in " carbon aryl ".
The example of carbon aryl is including but not limited to derived from those following carbon aryl:Benzene (i.e. phenyl) (C6), naphthalene (C10), (azulenes) (C10), anthracene (C14), luxuriant and rich with fragrance (C14), naphthonaphthalene (C18) pyrene (C16).
The example of the aryl comprising condensed ring (at least one its is aromatic ring) is including but not limited to derived from following group:Indane (such as 2,3- dihydro -1H- indenes) (C9), indenes (C9), different indenes (C9), tetrahydronaphthalene (1,2,3,4- naphthane (C10), acenaphthene (C12)、 Fluorenes (C13), non-that alkene (C13), vinegar phenanthrene (C15) and aceanthrene (C16).
Alternatively, annular atom can include one or more hetero atoms, such as in " heteroaryl ".The reality of bicyclic heteroaryl Example is including but not limited to derived from following those:
N1:Pyrroles (Pyrrole) (pyrroles, azole) (C5), pyridine (azine) (C6);
O1:Furan (oxole, oxole) (C5);
S1:Thiophene (thiophene) (thiophene, thiole) (C5);
N1O1:Azoles (C5), isoxazole (C5), different piperazine (C6);
N2O1:Diazole (furazan) (C5);
N3O1:Triazole (C5);
N1S1:Thiazole (C5), isothiazole (C5);
N2:Imidazoles (1,3- diazole) (C5), pyrazoles (1,2- diazole) (C5), pyridazine (1,2- diazine) (C6), pyrimidine (1,3- Diazine) (C6) (for example, cytosine, thymus pyrimidine, uracil), pyrazine (1,4-diazines) (C6);
N3:Triazole (C5), triazine (C6);And
N4:Tetrazolium (C5).
The example of the heteroaryl comprising condensed ring includes but is not limited to:
From following C9(there are 2 condensed ring):Benzofuran (O1), isobenzofuran (O1), indole (N1), iso-indoles (N1), benzazole (N1), indoline (N1), isoindoline (N1), purine (N4) (for example, adenine, guanine), benzimidazole (N2), indazole (N2), benzothiazole (N1O1), benzo isoxazole (N1O1), benzo dioxolen (benzodioxole) (O2), benzofuraxan (N2O1), benzotriazole (N3), benzothiophene (S1), benzothiazole (N1S1), diazosulfide (N2S);
From following C10(there are 2 condensed ring):Chromene (O1), heterochromatic alkene (O1), chromane (chroman) (O1), heterochromatic full (O1), benzodioxane (O2), quinoline (N1), isoquinolin (N1), quinolizine (N1), benzimidazole dihydrochloride (N1O1), benzodiazine (N2), pyrrole Pyridine pyridine (N2), quinoxaline (N2), quinazoline (N2), cinnolines (N2), phthalazines (phthalazine) (N2), naphthyridines (diaza Naphthalene, naphthyridine) (N2), pteridine (N4);
From following C11(there are 2 condensed ring):Benzodiazepine(N2);
From following C13(there are 3 condensed ring):Carbazole (N1), dibenzofurans (O1), dibenzothiophenes (S1), carboline (N2), pyridine (perimidine, perimidine) (N pah2), pyridine diindyl (N2);And
From following C14(there are 3 condensed ring):Acridine (N1), ton (xanthene) (O1), thioxanthene (S1), anthracene (oxanthrene)(O2), fen thiophene (phenoxathiin) (O1S1), azophenlyene (N2), azophenlyene (N1O1), phenothiazine (N1S1)、 Thianthrene (S2), phenanthridines (N1), phenanthroline (N2), azophenlyene (N2).
Above-mentioned group, no matter individually or a part for another substituent group, itself can alternatively be selected from them this Body and one or more substituent groups of the other substituent group being listed below.
Halogen:- F ,-Cl ,-Br and-I.
Hydroxyl:-OH.
Ether:- OR, wherein R are ether substituent group, for example, C1-7Alkyl (is also known as C1-7Alkoxyl, is discussed below), C3-20Heterocyclic radical (is also known as C3-20Heterocyclic oxy group) or C5-20Aryl (is also known as C5-20Aryloxy group), preferably C1-7Alkyl.
Alkoxyl:- OR, wherein R are alkyl, for example, C1-7Alkyl.C1-7The example of alkoxyl includes but is not limited to-OMe (methoxyl group) ,-OEt (ethyoxyl) ,-O (nPr) (positive propoxy) ,-O (iPr) (isopropoxy) ,-O (nBu) (n-butoxy) ,- O (sBu) (sec-butoxy) ,-O (iBu) (isobutoxy) and-O (tBu) (tert-butoxy).
Acetal:-CH(OR1)(OR2), wherein R1And R2It is independently acetal substitutent group, for example, C1-7Alkyl, C3-20Heterocyclic radical Or C5-20Aryl, preferably C1-7Alkyl, or, in the case of " ring-type " acetal groups, R1And R2Two being connected together with them Form the heterocycle with 4 to 8 annular atoms with them together with the carbon atom that individual oxygen atom is connected.The example of acetal groups includes But it is not limited to-CH (OMe)2、-CH(OEt)2With-CH (OMe) (OEt).
Hemiacetal:-CH(OH)(OR1), wherein R1It is hemiacetal substituent group, for example, C1-7Alkyl, C3-20Heterocyclic radical or C5-20 Aryl, preferably C1-7Alkyl.The example of hemiacetal group includes but is not limited to-CH (OH) (OMe) and-CH (OH) (OEt).
Ketal:-CR(OR1)(OR2), wherein R1And R2It is as defined for acetal, and R is ketal in addition to hydrogen Substituent group, for example, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, preferably C1-7Alkyl.The example of ketal group includes but does not limit In-C (Me) (OMe)2、-C(Me)(OEt)2、-C(Me)(OMe)(OEt)、-C(Et)(OMe)2、-C(Et)(OEt)2With-C (Et) (OMe)(OEt).
Hemiketal:-CR(OH)(OR1), wherein R1It is as limited for hemiacetal, and R is hemiketal in addition to hydrogen Substituent group, for example, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, preferably C1-7Alkyl.The example of hemiacetal group include but not It is limited to-C (Me) (OH) (OMe) ,-C (Et) (OH) (OMe) ,-C (Me) (OH) (OEt) and-C (Et) (OH) (OEt).
Oxo (ketone group, -one):=O.
Thioketone (Thione) (thio ketone, thioketone):=S.
Imino group (imines):=NR, wherein R are imino group substituent groups, for example, hydrogen, C1-7Alkyl, C3-20Heterocyclic radical or C5-20 Aryl, preferably hydrogen or C1-7Alkyl.The example of ester group including but not limited to=NH ,=NMe ,=Net and=NPh.
Formoxyl (formaldehyde, carbaldehyde, carboxaldehyde):- C (=O) H.
Acyl group (ketone group):- C (=O) R, wherein R are acyl substituents, for example, C1-7Alkyl (is also known as C1-7Alkane acyl Base), C3-20Heterocyclic radical (is also known as C3-20Heterocyclic acyl) or C5-20Aryl (is also known as C5-20Aroyl), preferably C1-7Alkane Base.The example of acyl group includes but is not limited to-C (=O) CH3(acetyl group) ,-C (=O) CH2CH3(propiono) ,-C (=O) C (CH3)3(tertiary bytyry) and-C (=O) Ph (benzoyl, benzophenone).
Carboxyl (carboxylic acid):- C (=O) OH.
Thiocarboxyl group (thiocarboxylic acid):- C (=S) SH.
Sulfydryl for carboxyl (mercaptan carboxyl, Thiolocarboxy) (sulfydryl for carboxylic acid (thiol carboxylic acid), thiolocarboxylic acid):- C (=O) SH.
Thion carboxyl (thiono carboxylic acid):- C (=S) OH.
Imidic acid (Imidic acid):- C (=NH) OH.
Hydroxamic acid:- C (=NOH) OH.
Ester (carboxylate (carboxylate, carboxylic acid ester), Epoxide carbonyl (oxycarbonyl)):- C (=O) OR, wherein R are ester substituent group, for example, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, preferably C1-7Alkyl.Ester group Example includes but is not limited to-C (=O) OCH3,-C (=O) OCH2CH3,-C (=O) OC (CH3)3With-C (=O) Oph.
Acyloxy (reverse ester):- OC (=O) R, wherein R are acyloxy substituent group, for example, C1-7Alkyl, C3-20Heterocyclic radical Or C5-20Aryl, preferably C1-7Alkyl.The example of acyloxy includes but is not limited to-OC (=O) CH3(acetoxyl group) ,-OC (=O) CH2CH3,-OC (=O) C (CH3)3,-OC (=O) Ph and-OC (=O) CH2Ph.
Epoxide carbonyloxy group (Oxycarboyloxy):- OC (=O) OR, wherein R are ester substituent group, for example, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, preferably C1-7Alkyl.The example of ester group includes but is not limited to-OC (=O) OCH3,-OC (=O) OCH2CH3,-OC (=O) OC (CH3)3With-OC (=O) Oph.
Amino:-NR1R2, wherein R1And R2It is independently amino-substituent, for example, hydrogen, C1-7Alkyl (is also known as C1-7Alkane Base amino or two C1-7Alkyl amino), C3-20Heterocyclic radical or C5-20Aryl, preferably H or C1-7Alkyl, or, in " ring-type " amino In the case of, R1And R2Form the heterocycle with 4 to 8 annular atoms together with the nitrogen-atoms that they are connected.Amino can be primary Amino (- NH2), secondary amino group (- NHR1) or tertiary amino (- NHR1R2), and in cationic form, can be quaternary ammonium (-+ NR1R2R3).The example of amino includes but is not limited to-NH2、-NHCH3、-NHC(CH3)2、-N(CH3)2、-N(CH2CH3)2With- NHPh.The example of cyclic amino include but is not limited to '-aziridino, azetidinyl, pyrrolidine simultaneously, piperidino (piperidino), Piperazino (piperazino), morpholino and thiomorpholine generation.
Acylamino- (carbamoyl, carbamyl, amino carbonyl, Methanamide):- C (=O) NR1R2, wherein R1And R2Solely It is on the spot amino-substituent, as defined in for amino.The example of acylamino- includes but is not limited to-C (=O) NH2,-C (= O)NHCH3,-C (=O) N (CH3)2,-C (=O) NHCH2CH3With-C (=O) N (CH2CH3)2, and acylamino-, wherein R1And R2 Form heterocycle structure together with the nitrogen-atoms that they are connected, such as exist, for example, piperidino carbonyl, morpholino carbonyl, thio In morpholino carbonyl and Piperazino carbonyl.
Thio acylamino (thiocarbamoyl):- C (=S) NR1R2, wherein R1And R2It is independently amino-substituent, As limited for amino.The example of acylamino- includes but is not limited to-C (=S) NH2,-C (=S) NHCH3,-C (=S) N (CH3)2With-C (=S) NHCH2CH3.
Acylamido (acylamino-):-NR1C (=O) R2, wherein R1It is amide substituents, for example, hydrogen, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, preferably hydrogen or C1-7Alkyl, and R2It is acyl substituent, for example, C1-7Alkyl, C3-20Heterocycle Base or C5-20Aryl, preferably hydrogen or C1-7Alkyl.The example of amide group includes but is not limited to-NHC (=O) CH3,-NHC (=O) CH2CH3With-NHC (=O) Ph.R1And R2Circulus can be formed together, such as exist, for example, succinimido, maleimide In amido and phthalimidyl:
Amino carbonyloxy group:- OC (=O) NR1R2, wherein R1And R2It is independently amino-substituent, as limited for amino 's.The example of amino carbonyloxy group includes but is not limited to-OC (=O) NH2,-OC (=O) NHMe ,-OC (=O) NMe2With-OC (=O) NEt2.
Urea groups:-N(R1)CONR2R3, wherein R2And R3It is independently amino-substituent, as defined in for amino, and R1It is Carbamido substituted base, for example, hydrogen, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, preferably hydrogen or C1-7Alkyl.The example of urea groups Including but not limited to-NHCONH2、-NHCONHMe、-NHCONHEt、-NHCONMe2、-NHCONEt2、-NMeCONH2、- NMeCONHMe、-NMeCONHEt、-NMeCONMe2With-NMeCONEt2.
Guanidine radicals:- NH-C (=NH) NH2.
Tetrazole radical:There are five yuan of aromatic rings of 4 nitrogen-atoms and a carbon atom,
Imino group:=NR, wherein R are imino group substituent groups, for example, hydrogen, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, Preferably H or C1-7Alkyl.The example of imino group including but not limited to=NH ,=NMe and=NEt.
Amidine (amidino groups):- C (=NR) NR2, wherein each R is amidine substituent group, for example, hydrogen, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, preferably H or C1-7Alkyl.The example of amidine group includes but is not limited to-C (=NH) NH2,-C (=NH) NMe2With-C (=NMe) NMe2.
Nitro:-NO2.
Nitroso-group:-NO.
Azido:-N3.
Cyano group (nitrile, nitrile, carbonitrile):-CN.
Isocyano group:-NC.
Cyanato (Cyanato):-OCN.
Isocyanato:-NCO.
Thiocyanogen (Thiocyano) (thiocyanogen):-SCN.
Isothiocyano (isothiocyano) (isothiocyano, isothiocyanato):-NCS.
Sulfydryl (Sulfhydryl) (mercaptan, thiol;Sulfydryl, mercapto):-SH.
Thioether (sulfide):- SR, wherein R are thioether substituent, for example, C1-7Alkyl (is also known as C1-7Alkylthio group), C3-20Heterocyclic radical or C5-20Aryl, preferably C1-7Alkyl.C1-7The example of alkylthio group includes but is not limited to-SCH3With-SCH2CH3.
Disulphide:- SS-R, wherein R are disulphide substituent group, for example, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Virtue Base, preferably C1-7Alkyl (also referred to as C1-7Alkyl disulfide).C1-7The example of alkyl disulfide group include but It is not limited to-SSCH3With-SSCH2CH3.
Sulfime base (sulfonium compound, sulfine) (sulfinyl, sulfoxide):- S (=O) R, wherein R are sulfime base substituent groups, example As C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, preferably C1-7Alkyl.The example of sulfime base group including but not limited to-S (= O)CH3With-S (=O) CH2CH3.
Sulfone (sulfonyl):- S (=O)2R, wherein R are sulfone substituent group, for example, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Virtue Base, preferably C1-7Alkyl, including, for example, fluorination or perfluorinate C1-7Alkyl.The example of sulfone group includes but is not limited to-S (=O)2CH3(mesyl) ,-S (=O)2CF3(trifyl, triflyl) ,-S (=O)2CH2CH3(ethylsulfonyl, Esyl) ,-S (=O)2C4F9(nine fluorine fourth sulfonyls, nonaflyl) ,-S (=O)2CH2CF3(trifluoro ethylsulfonyl, tresyl) ,- S (=O)2CH2CH2NH2(tauryl-, tauryl) ,-S (=O)2Ph (benzene sulfonyl, benzenesulfonyl (besyl)), 4- methylbenzene sulphur Acyl (tosyl (tosyl)), 4- chlorobenzenesulfonyl (chlorobenzenesulfonyl (closyl)), 4- bromophenylsulfonyl (bromobenzenesulfonyl (brosyl)), 4- nitrobenzophenone (nitrobenzenesulfonyl (nosyl)), 2- napsylate (naphthalene sulfonyl base, napsyl) and 5- diformazan Base amino-naphthalene -1- base sulphonic acid ester (dansyl (dansyl)).
Sulfinic acid (sulfino):- S (=O) OH ,-SO2H.
Sulfonic acid (sulfo group):- S (=O)2OH、-SO3H.
Sulfinic acid ester (sulfinate) (sulfinic acid ester, sulfinic acid ester):- S (=O) OR;Wherein R is sub- Sulfonate substituent, for example, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, preferably C1-7Alkyl.The example of sulfinate groups Including but not limited to-S (=O) OCH3(methoxyl group sulfinyl;Sulfinic acid methyl ester) and-S (=O) OCH2CH3(ethyoxyl sulfurous Acyl group;Sulfinic acid ethyl ester).
Sulphonic acid ester (sulfonate) (sulphonic acid ester, sulfonic acid ester):- S (=O)2OR, wherein R are sulfonic acid Ester substituent group, for example, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, preferably C1-7Alkyl.The example of sulfonate ester group include but It is not limited to-S (=O)2OCH3(methoxysulfonyl;Methylmesylate) and-S (=O)2OCH2CH3(ethoxysulfonyl;Sulfonic acid second Ester).
Sulfenyl epoxide:- OS (=O) R, wherein R are thionyl oxy substituents, for example, C1-7Alkyl, C3-20Heterocyclic radical Or C5-20Aryl, preferably C1-7Alkyl.The example of sulfurous acyloxy includes but is not limited to-OS (=O) CH3With-OS (=O) CH2CH3.
Sulfonyloxy:- OS (=O)2R, wherein R are sulfonyloxy substituent, for example, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, preferably C1-7Alkyl.The example of sulfonyloxy includes but is not limited to-OS (=O)2CH3(methanesulfonates) and-OS (= O)2CH2CH3(esilate).
Sulfuric ester:- OS (=O)2OR;Wherein R is sulfuric ester substituent group, for example, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Virtue Base, preferably C1-7Alkyl.The example of sulfate group includes but is not limited to-OS (=O)2OCH3With-SO (=O)2OCH2CH3.
Sulfonamides (sulfamyl) (sulfonamides (sulfamoyl);Sulfinic acid amide;Sulfenamide):- S (=O) NR1R2, Wherein R1And R2It is independently amino-substituent, as defined in for amino.The example of sulfonamides including but not limited to-S (= O)NH2,-S (=O) NH (CH3) ,-S (=O) N (CH3)2,-S (=O) NH (CH2CH3) ,-S (=O) N (CH2CH3)2With-S (=O) NHPh.
Sulfonamido (sulfonimide groups;Sulfonic acid amides;Sulfonamides):- S (=O)2NR1R2, wherein R1And R2It is independently Amino-substituent, as defined in for amino.The example of sulfonamido includes but is not limited to-S (=O)2NH2,-S (=O)2NH(CH3) ,-S (=O)2N(CH3)2,-S (=O)2NH(CH2CH3) ,-S (=O)2N(CH2CH3)2With-S (=O)2NHPh.
Sulfoamino-group:-NR1S (=O)2OH, wherein R1It is amino-substituent, as defined in for amino.The reality of sulfoamino-group Example includes but is not limited to-NHS (=O)2OH and-N (CH3) S (=O)2OH.
Sulfonamido (Sulfonamino):-NR1S (=O)2R, wherein R1It is amino-substituent, as defined for amino , and R is sulfonamide substituent, and for example, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, preferably C1-7Alkyl.Sulphonyl ammonia The example of base includes but is not limited to-NHS (=O)2CH3With-N (CH3) S (=O)2C6H5.
Sulfonamido (Sulfinamino):-NR1S (=O) R, wherein R1It is amino-substituent, as determined for amino Justice, and R is sulfinamino substituent, for example, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, preferably C1-7Alkyl.Sub- The example of sulfonamido includes but is not limited to-NHS (=O) CH3With-N (CH3) S (=O) C6H5.
Phosphino- (phosphine):-PR2, wherein R is phosphino- substituent group, for example ,-H, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, Preferably-H, C1-7Alkyl or C5-20Aryl.The example of phosphino- includes but is not limited to-PH2、-P(CH3)2、-P(CH2CH3)2、-P(t- Bu)2With-P (Ph)2.
Phospho:- P (=O)2.
Phosphoryl (phosphine oxide):- P (=O) R2, wherein R is phosphinyl substituent group, for example, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, preferably C1-7Alkyl or C5-20Aryl.The example of phosphoryl includes but is not limited to-P (=O) (CH3)2,-P (=O) (CH2CH3)2,-P (=O) (t-Bu)2With-P (=O) (Ph)2.
Phosphonic acids (phosphono):- P (=O) (OH)2.
Phosphonate ester (phosphono base ester):- P (=O) (OR)2, wherein R is phosphonate substituted base, for example ,-H, C1-7Alkyl, C3-20 Heterocyclic radical or C5-20Aryl, preferably-H, C1-7Alkyl or C5-20Aryl.The example of phosphonate groups includes but is not limited to-P (=O) (OCH3)2,-P (=O) (OCH2CH3)2,-P (=O) (O-t-Bu)2With-P (=O) (OPh)2.
Phosphoric acid (phosphonato):- OP (=O) (OH)2.
Phosphate ester (phosphonato ester):- OP (=O) (OR)2, wherein R is phosphate ester substituents, for example ,-H, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, preferably-H, C1-7Alkyl or C5-20Aryl.The example of bound phosphate groups includes but is not limited to-OP (=O) (OCH3)2,-OP (=O) (OCH2CH3)2,-OP (=O) (O-t-Bu)2With-OP (=O) (OPh)2.
Phosphorous acid:-OP(OH)2.
Phosphite ester:-OP(OR)2, wherein R is phosphite ester substituent group, for example ,-H, C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, preferably-H, C1-7Alkyl or C5-20Aryl.The example of phosphite group includes but is not limited to-OP (OCH3)2、-OP (OCH2CH3)2、-OP(O-t-Bu)2With-OP (OPh)2.
Phosphoramidite:-OP(OR1)-NR2 2, wherein R1And R2It is phosphoramidite substituent group, for example ,-H, (optionally substituted) C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, preferably-H, C1-7Alkyl or C5-20Aryl.The example of phosphoramidite group include but It is not limited to-OP (OCH2CH3)-N(CH3)2、-OP(OCH2CH3)-N(i-Pr)2With-OP (OCH2CH2CN)-N(i-Pr)2.
Phosphoramidate:- OP (=O) (OR1)-NR2 2, wherein R1And R2It is phosphoramidate substituent group, for example ,-H, (can Choose generation) C1-7Alkyl, C3-20Heterocyclic radical or C5-20Aryl, preferably-H, C1-7Alkyl or C5-20Aryl.Phosphoramidic acid ester group Example include but is not limited to-OP (=O) (OCH2CH3)-N(CH3)2,-OP (=O) (OCH2CH3)-N(i-Pr)2With-OP (= O)(OCH2CH2CN)-N(i-Pr)2.
Alkylidene
C3-12Alkylidene:As used in this article, term " C3-12Alkylidene " is related to by from having 3 to 12 carbon The identical carbon atoms of the hydrocarbon compound of atom (unless otherwise prescribed) remove two hydrogen atoms or each from two different carbon atoms Remove two toothed portions that obtained of a hydrogen atom, it can be aliphatic or alicyclic, and its can be saturation, part not Saturation or completely undersaturated.Therefore, the following subclass that term " alkylidene " inclusion is discussed below:Alkylene group, alkynylene, Ring alkylidene etc..
Straight chain saturation C3-12The example of alkylidene includes but is not limited to-(CH2)n-, wherein n is 3 to 12 integer, for example ,- CH2CH2CH2- (propylidene) ,-CH2CH2CH2CH2- (butylidene) ,-CH2CH2CH2CH2CH2- (pentylidene) and- CH2CH2CH2CH-2CH2CH2CH2- (heptamethylene).
Chain is saturated C3-12The example of alkylidene includes but is not limited to-CH (CH3)CH2-、-CH(CH3)CH2CH2-、-CH (CH3)CH2CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH(CH3)CH2CH2-、-CH(CH2CH3)-、-CH(CH2CH3)CH2- and- CH2CH(CH2CH3)CH2-.
The undersaturated C of linear fraction3-12Alkylidene (C3-12Alkenylene and alkynylene) example include but is not limited to-CH= CH-CH2-、-CH2- CH=CH2- ,-CH=CH-CH2-CH2- ,-CH=CH-CH2-CH2-CH2- ,-CH=CH-CH=CH- ,-CH =CH-CH=CH-CH2- ,-CH=CH-CH=CH-CH2-CH2- ,-CH=CH-CH2- CH=CH- ,-CH=CH-CH2-CH2-CH =CH- and-CH2-C≡C-CH2-.
The undersaturated C of branched fraction3-12Alkylidene (C3-12Alkenylene and alkynylene) example include but is not limited to-C (CH3)=CH-.-C(CH3)=CH-CH2- ,-CH=CH-CH (CH3)-and-C ≡ C-CH (CH3)-.
Alicyclic saturation C3-12Alkylidene (C3-12Ring alkylidene) example include but is not limited to cyclopentylene (for example ring is amyl- 1,3- subunit) and cyclohexylidene (such as hexamethylene -1,4- subunit).
The undersaturated C of cycloaliphatic moiety3-12Alkylidene (C3-12Ring alkylidene) example include but is not limited to cyclopentenylidene (such as 4- cyclopentenes -1,3- subunit), cyclohexadienylidene (such as 2- cyclohexene -1,4- subunit;3- cyclohexene -1,2- subunit;2, 5- cyclohexadiene -1,4- subunit).
Oxygen blocking group:Term " oxygen blocking group " refers to such part, and it shelters hydroxyl, and is many in this area Well known.Substantial amounts of suitable group is described in Greene, T.W.and Wuts, G.M., Protective Groups in Organic Synthesis,3rdPage 23 to 200 of Edition, John Wiley&Sons, Inc., 1999, it passes through to quote It is hereby incorporated by.Classification of special interest includes silyl ether (such as TMS, TBDMS), the methyl ether (such as THP) replacing With ester (such as acetass).
Carbamate nitrogen-protecting group group:Term " carbamate nitrogen-protecting group group " is related to such part, and it is sheltered Nitrogen in imine linkage, and be well known in the art.These groups have following structure:
Wherein R '10It is R as defined above.Substantial amounts of suitable group is described in Greene, T.W.and Wuts, G.M.,Protective Groups in Organic Synthesis,3rdEdition,John Wiley&Sons,Inc., 1999 page 503 to 549, it is incorporated herein by reference.
Hemiacetal amine nitrogen blocking group:Term " hemiacetal amine nitrogen blocking group " is related to the group with following structure:
Wherein R '10It is R as defined above.The substantial amounts of suitable group as amide blocking group is described in Greene,T.W.and Wuts,G.M.,Protective Groups in Organic Synthesis,3rdEdition, Page 633 to 647 of John Wiley&Sons, Inc., 1999, it is incorporated herein by reference.
Conjugate
The invention provides conjugate, it comprises to be connected to the PBD dimer of part unit via connector unit.In one kind In embodiment, connector unit includes extension unit (A), specificity unit (L1) and sept unit (L2).Connector unit one End is connected to part unit (L) and the other end is connected to PBD dimer compound (D).
On one side, Formula Il Ia shows such conjugate:
L-(A1 a-L1 s-L2 y-D)p(IIIa)
Or its pharmaceutical salts or solvate, wherein:
L is part unit;And
-A1 a-L1 s-L2 y- it is connector unit (LU), wherein:
-A1- it is extension unit,
A is 1 or 2,
-L1- it is specificity unit,
S is the integer that scope is 0 to 12,
-L2- it is sept unit,
Y is 0,1 or 2;
- D is PBD dimer;And
P is 1 to 20.
On the other hand, above-mentioned conjugate is shown in following formula III b:
It is also shown as:
L-(A1 a-L2 y(-L1 s)-D)p(IIIb)
Or its pharmaceutical salts or solvate, wherein:
L is part unit;And
-A1 a-L1 s(L2 y)-be connector unit (LU), wherein:
-A1- it is connected to extension unit (L2) extension unit,
A is 1 or 2,
-L1- it is connected to extension unit (L2) specificity unit,
S is the integer that scope is 0 to 12,
-L2- it is sept unit,
Y is 0,1 or 2;
- D is PBD dimer;And
P is 1 to 20.
Preference
Following preference can be used for all aspects of the invention as above, or can be related to single aspect.Permissible With any combinations, preference is combined together.
In one embodiment, conjugate has with following formula:
L-(A1 a-L1 s-L2 y-D)p
L-(A1 a-Ls 1-D)p
L-(A1-L1-D)pOr
L-(A1-D)p
Or its pharmaceutical salts or solvate, wherein L, A1、a、L1、s、L2, D, y and p be as above.
In one embodiment, part unit (L) is the target molecule being specifically incorporated on target cells Cell binding agent (CBA).Example molecule formula described below:
Wherein asterisk represents the junction point with drug unit (D), and CBA is cell binding agent, L1It is specificity unit, A1It is By L1It is connected to the extension unit of cell binding agent, L2It is sept unit, it is covalent bond, certainly eliminates group (self- Immolative group) or certainly eliminate group together with-OC (=O)-formation, and L2It is optional.If necessary ,- OC (=O)-be considered L1Or L2A part.
In another embodiment, part unit (L) is the target molecule being specifically incorporated on target cells Cell binding agent (CBA).Example molecule formula described below:
CBA–A1 a–L1 s–L2 y–*
Wherein asterisk represents the junction point with drug unit (D), and CBA is cell binding agent, L1It is specificity unit, A1It is Extension unit, it is by L1It is connected to cell binding agent, L2It is sept unit, it is covalent bond or certainly eliminates group, and a It is 1 or 2, s to be 0,1 or 2, and y is 0 or 1 or 2.
In embodiment illustrated above, L1Can be cleavable specificity unit, and can be referred to as, when depositing In one or more elimination group certainly, its activation when cut eliminates group (or multiple elimination group certainly) L certainly2From elimination " triggering thing ".As specificity unit L1When cut or when in L1And L2Between key (that is, covalent bond) be cut when, certainly disappear Except group release drug unit (D).
In another embodiment, part unit (L) is the target molecule being specifically incorporated on target cells Cell binding agent (CBA).Example molecule formula described below:
Wherein asterisk represents the junction point with medicine (D), and CBA is cell binding agent, L1It is connected to L2Specificity list Unit, A1It is by L2It is connected to the extension unit of cell binding agent, L2It is from eliminating group, and a is 1 or 2, s to be 1 or 2, and And y is 1 or 2.
In the various embodiments herein being discussed, L1And L2Characteristic can be very big difference.The choosing of these groups Selecting is characteristic based on them, and it can partly be decided by the condition at the position that conjugate is delivered.In specificity unit L1It is In the case of cleavable, select L1Structure and/or sequence so that what it was existed at target site (for example, target cell) place The effect of enzyme is cut.Can also be using by changing pH (for example sour or alkali labile), temperature or (for example right after irradiation Photo-labile) L that can cut1Unit.Cleavable L under reduction or oxidizing condition1Unit can be used for conjugate.
In some embodiments, L1The continuous sequence of an aminoacid or aminoacid can be comprised.Aminoacid sequence can To be the targeting substrate for enzyme.
In one embodiment, by the effect of enzyme, L1It is cleavable.In one embodiment, enzyme is esterase Or peptidase.For example, it is possible to pass through lysosomal protein enzyme, to cut L as cathepsin1.
In one embodiment, there is L2It is and formed from elimination group together with-C (=O) O-.Real at some Apply in mode ,-C (=O) O- is also from elimination group.
In one embodiment, in L1It is the cleavable and L of effect by enzyme2In the presence of, cleavage position In L1And L2Between key, thus, one or more from eliminate groups release drug units.
When it is present, can be by connecting L selected from following keys1And L2
- C (=O) NH-,
- C (=O) O-,
- NHC (=O)-,
- OC (=O)-,
- OC (=O) O-,
- NHC (=O) O-,
- OC (=O) NH-,
- NHC (=O) NH, and
- O- (glycosidic bond).
It is connected to L2L1Amino can be aminoacid N-terminal or can be derived from amino acid side chain amino, for example rely ammonia Sour amino acid side chain.
It is connected to L2L1Carboxyl can be aminoacid C-terminal or can be derived from amino acid side chain carboxyl, such as paddy ammonia Sour amino acid side chain.
It is connected to L2L1Hydroxyl can be derived from amino acid side chain hydroxyl, such as serine amino acids side chain.
In one embodiment ,-C (=O) O- and L2Form following group together:
Wherein asterisk represents the junction point with drug unit, and wavy line represents and L1Junction point, Y be-N (H)-,-O- ,- C (=O) N (H)-or-C (=O) O-, and n is 0 to 3.Phenylene ring is by one, two or three as described in this article Substituent group is optionally substituted.
In one embodiment, Y is NH.
In one embodiment, n is 0 or 1.Preferably, n is 0.
It is in the case that NH and n is 0 in Y, PAB carbonyl linker (PABC) can be referred to as from eliminating group.
When distal site within a fitting is activated, along line (for n=0) as follows, will permit from eliminating group Permitted release drug unit (that is, asymmetric PBD):
Wherein asterisk represents the connection with medicine, L*It is the activated form of the remainder of joint and not shown release Drug unit.These groups have the advantages that to make activation site and medical separation.
In another embodiment ,-C (=O) O- and L2Formed together selected from following group:
Wherein asterisk, wavy line, Y and n are as defined above.Each phenylene ring is by as described in this article one Individual, two or three substituent groups are optionally substituted.In one embodiment, the phenylene ring with Y substituent group is optionally substituted And not have the phenylene ring of Y substituent group be unsubstituted.
In another embodiment ,-C (=O) O- and L2Formed together selected from following group:
Wherein asterisk, wavy line, Y and n are as defined above, and E is O, S or NR, and D is N, CH or CR, and F be N, CH or CR.
In one embodiment, D is N.
In one embodiment, D is CH.
In one embodiment, E is O or S.
In one embodiment, F is CH.
In a preferred embodiment, in L1And L2Between covalent bond to be that cathepsin is unstable (for example, may be used Cutting) key.
In one embodiment, L1Comprise dipeptides.Aminoacid in dipeptides can be natural amino acid and non-natural Any combinations of aminoacid.In some embodiments, dipeptides comprises natural amino acid.When joint is that cathepsin is unstable In the case of joint, dipeptides is the action site of the cutting of cathepsin mediation.Thus dipeptides is the identification of cathepsin Site.
In one embodiment, in dipeptides ,-NH-X1-X2- CO-, in group-X1-X2- be selected from:
- Phe-Lys-,
- Val-Ala-,
- Val-Lys-,
- Ala-Lys-,
- Val-Cit-,
- Phe-Cit-,
- Leu-Cit-,
- Ile-Cit-,
- Phe-Arg-, and
-Trp-Cit-;
Wherein Cit is citrulline.In such dipeptides ,-NH- is X1Amino, and CO is X2Carbonyl.
Preferably, in dipeptides-NH-X1-X2Group-X in-CO-1-X2- be selected from:
- Phe-Lys-,
- Val-Ala-,
- Val-Lys-,
- Ala-Lys-, and
-Val-Cit-.
Most preferably, in dipeptides-NH-X1-X2Group-X in-CO-1-X2- it is-Phe-Lys-, Val-Cit or-Val- Ala-.
Other dipeptides combination interested includes:
- Gly-Gly-,
- Pro-Pro-, and
-Val-Glu-.
Can be using the combination of other dipeptides, including those combinations by descriptions such as Dubowchik, it is incorporated by reference into This.
In one embodiment, in the appropriate case, amino acid side chain is subject to chemoproection.Side chain protecting group is permissible It is group as discussed below.The shielded aminoacid sequence of cleavage can be passed through.For example, it is possible to pass through cathepsin Cutting comprises the dipeptide sequence of the Lys residue of Boc side chain protected.
Blocking group for the side chain of aminoacid is well known in the art and is described in Novabiochem Catalog.Other blocking group strategy is set forth in Protective groups in Organic Synthesis, Greene and Wuts.
The possible side chain protecting group of the aminoacid for those with reactive side chain function described below:
Arg:Z、Mtr、Tos;
Asn:Trt、Xan;
Asp:Bzl、t-Bu;
Cys:Acm、Bzl、Bzl-OMe、Bzl-Me、Trt;
Glu:Bzl、t-Bu;
Gln:Trt、Xan;
His:Boc、Dnp、Tos、Trt;
Lys:Boc、Z-Cl、Fmoc、Z;
Ser:Bzl、TBDMS、TBDPS;
Thr:Bz;
Trp:Boc;
Tyr:Bzl、Z、Z-Br.
In one embodiment, by-X2- it is indirectly coupled to drug unit.In such embodiment, there is interval Thing unit L2.
In one embodiment, dipeptides is utilized in conjunction with from elimination group (sept unit) with one or more.Can To be connected to-X by one or more from elimination group2-.
Exist from the case of eliminate group, by-X2- be directly connected in from elimination group.In one embodiment, By-X2- be connected to from the group Y eliminating group.Preferably, by group-X2- CO- is connected to Y, and wherein Y is NH.
In one embodiment, by-X1- it is directly connected in A1.Preferably, by group NH-X1-(X1Amino terminal) It is connected to A1.A1Functional group-CO- can be comprised, thus formed that there is-X1- amide linker.
In one embodiment, L1And L2Together with-OC (=O)-comprise group-X1-X2-PABC-.PABC group It is directly connected in drug unit.In one embodiment, form group-Phe-Lys-PABC- together with dipeptides from elimination group, It illustrates hereafter:
Wherein asterisk represents the junction point with drug unit, and wavy line represents and L1The junction point of remainder or With A1Junction point.Preferably, wavy line represents and A1Junction point.
Alternatively, form group-Val-Ala-PABC- together with dipeptides from elimination group, it illustrates hereafter:
Wherein asterisk and wavy line are as hereinbefore defined.
In another embodiment, L1And L2Together with-OC (=O)-represent:
Wherein asterisk represents the junction point with drug unit, and wavy line represents and A1Junction point, Y is covalent bond or sense Group, and E is group easily slit, thus activation is from elimination group.
E is selected to make group easily slit, for example, by light or by the effect of enzyme.E can be-NO2Or glucuronic acid (for example, β-glucuronic acid).The former can be to the susceptible of nitroreductase, and the latter can be to the work of beta-Glucuronidase With sensitivity.
Group Y can be covalent bond.
Group Y can be functional group, and it is selected from:
- C (=O)-,
- NH-,
- O-,
- C (=O) NH-,
- C (=O) O-,
- NHC (=O)-,
- OC (=O)-,
- OC (=O) O-,
- NHC (=O) O-,
- OC (=O) NH-,
- NHC (=O) NH-,
- NHC (=O) NH,
- C (=O) NHC (=O)-,
SO2, and
-S-.
Group Y is preferably NH- ,-CH2- ,-O- and-S-.
In some embodiments, L1And L2Together with-OC (=O)-represent:
Wherein asterisk represents the junction point with drug unit, and wavy line represents the junction point with A, and Y is covalent bond or sense Group, and E is glucuronic acid (for example, β-glucuronic acid).Y is preferably selected from the functional group of-NH-.
In some embodiments, L1And L2Represent together:
Wherein asterisk represents and L2Remainder or drug unit junction point, wavy line represents and A1Junction point, Y It is covalent bond or functional group, and E is glucuronic acid (for example, β-glucuronic acid).Y is preferably selected from NH- ,-CH2-、-O- Functional group with-S-.
In some further embodiments, Y is functional group as described above, and above-mentioned functional group is connected to amino Acid, and aminoacid is connected to extension unit A1.In some embodiments, aminoacid is Beta-alanine.Such In embodiment, aminoacid is equally considered a part for extension unit.
It is indirectly connected with specificity unit L via extension unit1With part unit.
Can be by connecting L selected from following key1And A1
- C (=O) NH-,
- C (=O) O-,
- NHC (=O)-,
- OC (=O)-,
- OC (=O) O-,
- NHC (=O) O-,
- OC (=O) NH-, and
- NHC (=O) NH-.
In one embodiment, group A1It is:
Wherein asterisk represents and L1Junction point, wavy line represents the junction point with part unit, and n is 0 to 6.? In a kind of embodiment, n is 5.
In one embodiment, group A1It is:
Wherein asterisk represents and L1Junction point, wavy line represents the junction point with part unit, and n is 0 to 6.? In a kind of embodiment, n is 5.
In one embodiment, group A1It is:
Wherein asterisk represents and L1Junction point, wavy line represents the junction point with part unit, and n is 0 or 1, and m is 0 to 30.In a preferred embodiment, n is 1 and m to be 0 to 10,1 to 8, preferably 4 to 8, most preferably 4 or 8.
In one embodiment, group A1It is:
Wherein asterisk represents and L1Junction point, wavy line represents the junction point with part unit, and n is 0 or 1, and m is 0 to 30.In a preferred embodiment, n is 1 and m to be 0 to 10,1 to 8, preferably 4 to 8, most preferably 4 or 8.
In one embodiment, group A1It is:
Wherein asterisk represents and L1Junction point, wavy line represents the junction point with part unit, and n is 0 to 6.? In a kind of embodiment, n is 5.
In one embodiment, group A1It is:
Wherein asterisk represents and L1Junction point, wavy line represents the junction point with part unit, and n is 0 to 6.? In a kind of embodiment, n is 5.
In one embodiment, group A1It is:
Wherein asterisk represents and L1Junction point, wavy line represents the junction point with part unit, and n is 0 or 1, and m is 0 to 30.In a preferred embodiment, n is 1 and m to be 0 to 10,1 to 8, preferably 4 to 8, most preferably 4 or 8.
In one embodiment, group A1It is:
Wherein asterisk represents and L1Junction point, wavy line represents the junction point with part unit, and n is 0 or 1, and m is 0 to 30.In a preferred embodiment, n is 1 and m to be 0 to 10,1 to 8, preferably 4 to 8, most preferably 4 or 8.
In one embodiment, in part unit and A1Between connection be thiol residue and A by part unit1 Maleimide base group.
In one embodiment, in part unit and A1Between connection be:
Wherein asterisk represents and A1、L1、L2Or the junction point of the remainder of D, and wavy line represents and part unit The junction point of remainder.In this embodiment, S atom is typically derived from part unit.
In above-mentioned every kind of embodiment, it is possible to use interchangeable functional group is substituting maleimide described below Class group:
Wherein wavy line represents the junction point (as previously mentioned) with part unit, and asterisk represents and A1The residue of group Part or and L1、L2Or the key of D.
In one embodiment, substitute maleimide group with following group:
Wherein wavy line represents the junction point with part unit, and asterisk represents and A1The remainder of group or and L1、 L2Or the key of D.
In one embodiment, with selected from following group, optionally along with part unit, (for example, cell combines for it Agent) together, to substitute maleimide group:
- C (=O) NH-,
- C (=O) O-,
- NHC (=O)-,
- OC (=O)-,
- OC (=O) O-,
- NHC (=O) O-,
- OC (=O) NH-,
- NHC (=O) NH-,
- NHC (=O) NH,
- C (=O) NHC (=O)-,
- S-,
- S-S-,
-CH2C (=O)-,
- C (=O) CH2-,
=N-NH-, and
- NH-N=.
Wherein ,-C (=O) CH2- can be preferred, particularly when carbonyl is incorporated into NH-.
In one embodiment, with selected from following group, it optionally along with part unit together, to substitute Malaysia Acid imide group:
Wherein wavy line represents the junction point with part unit or and A1The key of the remainder of group, and asterisk represents Another junction point or and A with part unit1The key of the remainder of group.
WO2005/082023 describes be suitable for L1It is connected to the other groups of cell binding agent.
In one embodiment, there is extension unit A1, there is specificity unit L1And there is not sept unit L2.Therefore, it is directly connected to L via key1And drug unit.Equally, in this embodiment, L2It is key.
Can be by connecting L selected from following key1And D:
- C (=O) N<,
- C (=O) O-,
- NHC (=O)-,
- OC (=O)-,
- OC (=O) O-,
- NHC (=O) O-,
- OC (=O) N<, and
- NHC (=O) N<,
Wherein N<Or O- is the part of D.
In one embodiment, preferably by connecting L selected from following key1And D:
- C (=O) N<, and
- NHC (=O)-.
In one embodiment, L1Comprise dipeptides and one end of dipeptides is connected to D.As described above, the ammonia in dipeptides Base acid can be any combinations of natural amino acid and alpha-non-natural amino acid.In some embodiments, dipeptides comprises natural ammonia Base acid.In the case that joint is the unstable joint of cathepsin, dipeptides is the work of the cutting for cathepsin mediation Use site.Therefore dipeptides is the recognition site of cathepsin.
In one embodiment, in dipeptides-NH-X1-X2Group-X in-CO-1-X2- be selected from:
- Phe-Lys-,
- Val-Ala-,
- Val-Lys-,
- Ala-Lys-,
- Val-Cit-,
- Phe-Cit-,
- Leu-Cit-,
- Ile-Cit-,
- Phe-Arg-, and
-Trp-Cit-;
Wherein Cit is citrulline.In such dipeptides ,-NH- is X1Amino, and CO is X2Carbonyl.
Preferably, in dipeptides-NH-X1-X2Group-X in-CO-1-X2- be selected from:
- Phe-Lys-,
- Val-Ala-,
- Val-Lys-,
- Ala-Lys-, and
-Val-Cit-.
Most preferably, in dipeptides-NH-X1-X2Group-X in-CO-1-X2- it is-Phe-Lys- or-Val-Ala-.
Other dipeptides combination interested includes:
- Gly-Gly-,
- Pro-Pro-, and
-Val-Glu-.
Can be using the combination of other dipeptides, including those described above combination.
In one embodiment, L1- D is:
-NH-X1-X2-CO-N<*
Wherein-NH-X1-X2- CO is dipeptides ,-N<It is a part for drug unit, asterisk represents the residue with drug unit Partial junction point, and wavy line represents and L1The junction point of remainder or and A1Junction point.Preferably, wavy line Represent and A1Junction point.
In one embodiment, dipeptides is val-ala and L1- D is:
Wherein asterisk ,-N<It is as defined above with wavy line.
In one embodiment, dipeptides is Phe-Lys and L1- D is:
Wherein asterisk ,-N<It is as defined above with wavy line.
In one embodiment, dipeptides is valine-citrulline.
In one embodiment, group A1-L1It is:
Wherein, asterisk represents and L2Or the junction point of D, wavy line represents the junction point with part unit, and n be 0 to 6.In one embodiment, n is 5.
In one embodiment, group A1-L1It is:
Wherein asterisk represents and L2Or the junction point of D, wavy line represents the junction point with part unit, and n is 0 to 6. In one embodiment, n is 5.
In one embodiment, group A1-L1It is:
Wherein asterisk represents and L2Or the junction point of D, wavy line represents the junction point with part unit, and n is 0 or 1, and M is 0 to 30.In a preferred embodiment, n is 1 and m to be 0 to 10,1 to 8, preferably 4 to 8, most preferably 4 or 8.
In one embodiment, group A1-L1It is:
Wherein asterisk represents and L2Or the junction point of D, wavy line represents the junction point with part unit, and n is 0 or 1, and M is 0 to 30.In a preferred embodiment, n is 1 and m to be 0 to 10,1 to 7, preferably 3 to 7, most preferably 3 or 7.
In one embodiment, group A1-L1It is:
Wherein asterisk represents and L2Or the junction point of D, wavy line represents the junction point with part unit, and n is 0 to 6. In one embodiment, n is 5.
In one embodiment, group A1-L1It is:
Wherein asterisk represents and L2Or the junction point of D, wavy line represents the junction point with part unit, and n is 0 to 6. In one embodiment, n is 5.
In one embodiment, group A1-L1It is:
Wherein asterisk represents and L2Or the junction point of D, wavy line represents the junction point with part unit, and n is 0 or 1, and M is 0 to 30.In a preferred embodiment, n is 1 and m to be 0 to 10,1 to 8, preferably 4 to 8, most preferably 4 or 8.
In one embodiment, group A1-L1It is:
Wherein asterisk represents and L2Or the junction point of D, wavy line represents the junction point with part unit, and n is 0 or 1, and M is 0 to 30.In a preferred embodiment, n is 1 and m to be 0 to 10,1 to 8, preferably 4 to 8, most preferably 4 or 8.
In one embodiment, group L-A1-L1It is:
Wherein asterisk represents and L2Or the junction point of D, S is the sulfenyl of part unit, wavy line represent and part unit Remainder junction point, and n is 0 to 6.In one embodiment, n is 5.
In one embodiment, group L-A1-L1It is:
Wherein asterisk represents and L2Or the junction point of D, S is the sulfenyl of part unit, and wavy line represents and part unit The junction point of remainder, and n is 0 to 6.In one embodiment, n is 5.
In one embodiment, group L-A1-L1It is:
Wherein asterisk represents and L2Or the junction point of D, S is the sulfenyl of part unit, and wavy line represents and part unit The junction point of remainder, n is 0 or 1, and m is 0 to 30.In a preferred embodiment, n be 1 and m be 0 to 10th, 1 to 8, preferably 4 to 8, most preferably 4 or 8.
In one embodiment, group L-A1-L1It is:
Wherein asterisk represents and L2Or the junction point of D, wavy line represents the junction point with part unit, and n is 0 or 1, and M is 0 to 30.In a preferred embodiment, n is 1 and m to be 0 to 10,1 to 7, preferably 4 to 8, most preferably 4 or 8.
In one embodiment, group L-A1-L1It is:
Wherein asterisk represents and L2Or the junction point of D, wavy line represents the junction point with the remainder of part unit, and And n is 0 to 6.In one embodiment, n is 5.
In one embodiment, group L-A1-L1It is:
Wherein asterisk represents and L2Or the junction point of D, wavy line represents the junction point with the remainder of part unit, and And n is 0 to 6.In one embodiment, n is 5.
In one embodiment, group L-A1-L1It is:
Wherein asterisk represents and L2Or the junction point of D, wavy line represents the junction point with the remainder of part unit, n It is 0 or 1, and m is 0 to 30.In a preferred embodiment, n is 1 and m is 0 to 10,1 to 8, preferably 4 to 8, Preferably 4 or 8.
In one embodiment, group L-A1-L1It is:
Wherein asterisk represents and L2Or the junction point of D, wavy line represents the junction point with the remainder of part unit, n It is 0 or 1, and m is 0 to 30.In a preferred embodiment, n is 1 and m is 0 to 10,1 to 8, preferably 4 to 8, Preferably 4 or 8.
In one embodiment, extension unit is the acetyl amine unit with following formula:
-CH2-CO-N-*
Wherein asterisk represents and the remainder of extension unit, L1Or the junction point of D, and wavy line represents and part The junction point of unit.
Linker-drug
In other embodiments, linker-drug compound is provided, is used for being incorporated into part unit.In a kind of embodiment party In formula, designed joint-medical compoundss are used for being connected to cell binding agent.
In one embodiment, medicine linker compounds have with following formula:
Wherein asterisk represents the junction point with drug unit (D, as defined above), G1It is to be formed with part unit even Extension group (the A connecing1), L1It is specificity unit, L2(sept unit) is covalent bond or together with-OC (=O)-formed From elimination group.
In another embodiment, medicine linker compounds have with following formula:
G1-L1-L2-*
Wherein asterisk represents the junction point with drug unit (D), G1It is to form the extension list being connected with part unit First (A1), L1It is specificity unit, L2(sept unit) is covalent bond or one or more elimination group certainly.
L1And L2It is as defined above.Referenced herein it is connected to A1Can be understood as referring to be connected to G1.
In one embodiment, wherein L1Comprise aminoacid, the side chain of this aminoacid can be protected.Can use any Suitable blocking group.In one embodiment, other blocking group (if present) being used in compound remove Side chain protecting group.In other embodiments, blocking group can orthogonal with other blocking groups in molecule (if deposited ).
Suitable blocking group for amino acid side chain includes being described in Novabiochem Catalog2006/2007 In those groups.The blocking group for the unstable joint of cathepsin is also discussed in Dubowchik et al.
In some embodiments of the present invention, group L1Including Lys amino acid residue.Can be with Boc or Alloc protection Group is protecting the side chain of this aminoacid.Boc blocking group is most preferred.
After reacting with part unit (for example, cell binding agent), functional group G1Form linking group.
In one embodiment, functional group G1It is or comprise amino, carboxylic acid, hydroxyl, sulfydryl or maleimide base group, For with part unit on suitable radical reaction.In a preferred embodiment, G1Comprise maleimide base group.
In one embodiment, group G1It is alkyl maleimide group.This group is applied to and is present in cell (for example it is present in antibody) sulfydryl, particularly cysteine sulfydryl reaction in bonding agent.
In one embodiment, group G1It is:
Wherein asterisk represents and L1、L2Or the junction point of D, and n is 0 to 6.In one embodiment, n is 5.
In one embodiment, group G1It is:
Wherein asterisk represents and L1、L2Or the junction point of D, and n is 0 to 6.In one embodiment, n is 5.
In one embodiment, group G1It is:
Wherein asterisk represents and L1Junction point, n is 0 or 1, and m is 0 to 30.In a preferred embodiment, N is 1 and m to be 0 to 10,1 to 2, preferably 4 to 8 and most preferably 4 or 8.
In one embodiment, group G1It is:
Wherein asterisk represents and L1Junction point, n is 0 or 1, and m is 0 to 30.In a preferred embodiment, N is 1 and m to be 0 to 10,1 to 8, preferably 4 to 8 and most preferably 4 or 8.
In one embodiment, group G1It is:
Wherein asterisk represents and L1、L2Or the junction point of D, and n is 0 to 6.In one embodiment, n is 5.
In one embodiment, group G1It is:
Wherein asterisk represents and L1、L2Or the junction point of D, and n is 0 to 6.In one embodiment, n is 5.
In one embodiment, group G1It is:
Wherein asterisk represents and L1Junction point, n is 0 or 1, and m is 0 to 30.In a preferred embodiment, N is 1 and m to be 0 to 10,1 to 2, preferably 4 to 8 and most preferably 4 or 8.
In one embodiment, group G1It is:
Wherein asterisk represents and L1Junction point, n is 0 or 1, and m is 0 to 30.In a preferred embodiment, N is 1 and m to be 0 to 10,1 to 8, preferably 4 to 8 and most preferably 4 or 8.
In above-mentioned every kind of embodiment, it is possible to use interchangeable functional group is replacing maleimide shown below Group:
Wherein asterisk represents the key with the remainder of G group.
In one embodiment, substitute maleimide group with following group:
Wherein asterisk represents the key with the remainder of G group.
In one embodiment, with substituting maleimide base group selected from following group:
- C (=O) OH,
- OH,
-NH2,
- SH,
- C (=O) CH2X, wherein X are Cl, Br or I,
- CHO,
-NHNH2,
- C ≡ CH, and
-N3(azide).
Wherein ,-C (=O) CH2X can be preferred, particularly when carbonyl is incorporated into-NH-.
In one embodiment, there is L1, and G1It is-NH2,-NHMe ,-COOH ,-OH or-SH.
In one embodiment, wherein there is L1, G1It is-NH2Or-NHMe.Any group can be L1Aminoacid sequence The N-terminal of row.
In one embodiment, there is L1And G1It is-NH2, and L1It is aminoacid sequence-X1-X2- (such as institute above Definition).
In one embodiment, there is L1And G1It is COOH.This group can be L1The C-terminal of aminoacid sequence.
In one embodiment, there is L1And G1It is OH.
In one embodiment, there is L1And G1It is SH.
Can be by group G1It is another kind of functional group from a kind of functional group conversions.In one embodiment, there is L1And G1It is-NH2.This group can be converted into another kind of group G comprising maleimide base group1.For example, group-NH2Permissible With those G comprising maleimide illustrated above1The acid of group or activated acids (for example, N- butanimide form) are anti- Should.
Therefore, it can group G1Change into more suitable for the functional group with part unit process.
As described above, in one embodiment, there is L1And G1It is-NH2,-NHMe ,-COOH ,-OH or-SH.Entering In the embodiment of one step, to provide these groups with chemoproection form.Therefore, chemoproection form is to be provided with functional group Joint precursor.
In one embodiment, G1It is chemoproection form-NH2.Can be protected with carbamate protecting group Above-mentioned group.Carbamate protecting group can be selected from group consisting of:
Alloc, Fmoc, Boc, Troc, Teoc, Cbz and PNZ.
Preferably, in G1It is-NH2In the case of, protect it with Alloc or Fmoc group.
In one embodiment, in G1It is-NH2In the case of, protect it with Fmoc group.
In one embodiment, blocking group is identical with the carbamate protecting group of end-capping group.
In one embodiment, blocking group and the carbamate protecting group of end-capping group differ.Here is real Apply in mode it is preferred that blocking group is can under conditions of the carbamate protecting group not removing end-capping group Remove.
Chemical protecting group can be removed to provide functional group, thus forming the connection with part unit.Alternatively, then This functional group conversions can be become another kind of functional group (as described above).
In one embodiment, active group is amine.This amine is preferably the N-terminal amine of peptide, and can be the present invention The N-terminal amine of preferred dipeptides.
Active group can be made to react to produce for forming the functional group being connected with part unit.
In other embodiments, connector unit is the precursor of the connector unit of active group.In this embodiment In, connector unit comprises active group, and it is protected by way of blocking group.Blocking group can be removed to provide tool The connector unit of active group.
In the case that active group is amine, blocking group can be amine protecting group group, such as in Green and Wuts Those amine protecting group groups of description.
Preferably orthogonal with other blocking groups (if present) of blocking group in connector unit.
In one embodiment, blocking group is orthogonal with end-capping group.Therefore, removable active group blocking group, Retain end-capping group simultaneously.In other embodiments, with for removing those condition identicals of end-capping group under the conditions of, Blocking group and end-capping group are removable.
In one embodiment, connector unit is:
Wherein asterisk represents the junction point with drug unit, and wavy line represents the company with the remainder of connector unit Contact, (as being suitable for) or and G1Junction point.Preferably, wavy line represents and G1Junction point.
In one embodiment, connector unit is:
Wherein asterisk and wavy line are as defined above.
WO2005/082023 describes be applied in L1Form other senses of connection and cell binding agent between Group.
Part unit
Part unit can be any species, and include specifically being incorporated into the protein of target molecule, polypeptide, peptide and Non- peptide reagent.In some embodiments, part unit can be protein, polypeptide or peptide.In some embodiments, part Unit can be ring type polypeptide.These part units can include antibody or comprise the anti-of at least one target molecule-binding site The fragment of body, lymphokine, hormone, somatomedin or any other cell binding molecule that can specifically be incorporated into target Or material.Part unit is also referred to as " bonding agent " or " targeting agent ".
Term " specifically combining " and " specific binding " refer to antibody or other protein, polypeptide or peptide be bound to pre- The molecule (for example, antigen) first determining.Generally, antibody or other molecules are with least about 1x107M-1Affinity be bound to predetermined Molecule, and to be attached to the non-specific molecules different from predetermined molecule or the molecule that is closely related (for example, than it BSA, casein) the affinity of the high at least twice of affinity be bound to predetermined molecule.
The example of part unit include for using those described reagent, be incorporated in WO2007/085930 in Herein.
In some embodiments, part unit is the cell binding agent of the extracellular target being bound on cell.Such thin Born of the same parents' bonding agent can be protein, polypeptide, peptide or non-peptide reagent.In some embodiments, cell binding agent can be albumen Matter, polypeptide or peptide.In some embodiments, cell binding agent can be ring type polypeptide.Cell binding agent can also be antibody Or the Fab of antibody.Therefore, in one embodiment, the invention provides antibody-drug conjugates (ADC).
In one embodiment, antibody is monoclonal antibody;Chimeric antibody;Humanized antibody;Human antibody;Or it is single-stranded Antibody.In one embodiment, antibody is the fragment with biological activity of one of these antibody.The example bag of above-mentioned fragment Include Fab, Fab', F (ab')2With Fv fragment.
Antibody can be Homodimer, domain antibodies (DAB) or single-chain antibody.
In one embodiment, antibody is monoclonal antibody.
Those antibody including described in WO2005/082023 for the antibody of the present invention, are incorporated in this article. Particularly preferably it is directed to those antibody of tumor associated antigen.The example of those antigens being known in the art include but not It is limited to the tumor associated antigen that those propose in WO2005/082023.See, e.g., the 41-55 page.
In some embodiments, design conjugate, targets neoplastic cells are come with the cell surface antigen via them.Anti- Former can be to be over-expressed, or the cell surface antigen being expressed in abnormal time or cell type.Preferably, target antigen is only It is expressed on proliferative cell (preferably tumor cell);However, this is seldom observed in practice.Therefore, it is typically based on Differential expression between hypertrophy and health tissues is selecting target antigen.
Produce the antibody for targeting specific tumors related antigen to include:
Cripto, CD19, CD20, CD22, CD30, CD33, glycoprotein NMB, CanAg, Her2 (ErbB2/Neu), CD56 (NCAM), CD70, CD79, CD138, PSCA, PSMA (prostate specific membrane antigen), BCMA, CD62L, EphB2, black Plain transferrinss (Melanotransferin), Muc16 and TMEFF2.
Part unit is connected to connector unit.In one embodiment, part unit is connected to the A of connector unit (such as Fruit exists).
In one embodiment, the connection between part unit and connector unit is by thioether bond.
In one embodiment, the connection between part unit and connector unit is by disulfide bond.
In one embodiment, the connection between part unit and connector unit is by amido link.
In one embodiment, the connection between part unit and connector unit is by ester bond.
In one embodiment, in the sulfydryl of the cysteine residues of part unit and the maleimide of connector unit It is formed at the connection between part unit and joint between base.
The cysteine residues of part unit can be used for being connected to be formed with the functional group reactionses of connector unit.At other In embodiment, such as in the case that part unit is antibody, the sulfydryl of antibody can participate in interchain disulfide bond.With joint Before the functional group reactionses of unit, by for example processing antibody with DTT, these interchain keys can be changed into free sulfhydryl group.
In some embodiments, cysteine residues are introduced heavy chain or the light chain of antibody.In antibody weight or light chain For being included in disclosed U.S. Application No. 2007-0092940 and international monopoly by replacing the position inserting cysteine Those described in open WO2008070593, are incorporated in herein.
Therapeutic Method
The compound of the present invention can be used in Therapeutic Method.Additionally provide a kind of Therapeutic Method, the method includes controlling The compound treating effective dose Formulas I gives experimenter in need for the treatment of.Term " therapeutically effective amount " is enough to show to benefits subjects The amount at place.Above-mentioned benefit can be at least to improve a kind of symptom.The actual amount giving and the speed giving and time course will Depending on property to be treated and seriousness.Treatment prescription, such as dosage determine, are the responsibilities in omni-doctor and other doctors In the range of.
Can (simultaneously or sequentially, it depends on disease to be treated) to give chemical combination together alone or together with other treatment Thing.The example for the treatment of and therapy including but not limited to chemotherapy (give activating agent, including, for example, medicine);Surgical operation;And X-ray therapy.
According to the present invention's with pharmaceutical composition used according to the present invention, except active component (i.e. the compound of Formulas I) with Outward, pharmaceutical excipient, carrier, buffer agent, stabilizer or other materials well known to the skilled person can also be comprised. Above-mentioned material should be effect that is nontoxic and should not interfere with active component.The precise characteristics of carrier or other materials will depend upon Give approach, it can be oral, or by injection, such as injection of skin, subcutaneous injection or intravenous injection.
Pharmaceutical composition for being orally administered to can be tablet, capsule, powder or liquid form.Tablet can comprise Solid carrier or adjuvant.Composition of liquid medicine generally comprise liquid-carrier for example water, oil, animal or plant oil, mineral oil or Artificial oil.Normal saline solution, dextrose or other sugar juices or glycolss such as ethylene glycol, propylene glycol or poly- second two can be included Alcohol.Capsule can comprise solid carrier such as gelatin.
For intravenouss, skin or subcutaneous injection, or the injection at painful position, active component will have parenteral The form of acceptable aqueous solution, it is pyrogen-free and has suitable pH, isotonicity and stability.Those skilled in the art Can be using for example, isotonic carrier such as sodium chloride injection, ringer's injection, lactated ringer's injection to be prepared well Suitable solution.As needed, preservative, stabilizer, buffer agent, antioxidant and/or other additives can be included.
Compound and conjugate can be used to treat proliferative disease and autoimmune disease.Term " proliferative disease " is related to Undesirable excessively or abnormal cell unwanted or uncontrolled hyperplasia, e.g., angiogenic or Hyperplastic growth is (no Pipe is external or internal).
The example of proliferative disorders is including but not limited to optimum, deteriorate front and malignant cell proliferation, including but not limited to newly Biological and tumor (for example, histiocytoma, glioma, astrocytoma, osteoma), cancer (for example pulmonary carcinoma, small cell lung cancer, Human primary gastrointestinal cancers, intestinal cancer, colon cancer, breast carcinoma, ovarian cancer, carcinoma of prostate, carcinoma of testis, hepatocarcinoma, renal carcinoma, bladder cancer, cancer of pancreas, brain Cancer, sarcoma, osteosarcoma, Kaposi sarcoma, melanoma), leukemia, psoriasiss, osteopathia, fibroproliferative disease (such as connective The fibroproliferative disease of tissue) and atherosclerosiss.Other cancers interested include but is not limited to Hematological Malignancies As leukemia and lymphoma, such as non-Hodgkin lymphoma, and hypotype such as DLBCL, marginal zone, overcoat area (mantle zone) and Follicularis Hodgkin lymphoma, AML, and B or other cancers of T cell origin.
The example of autoimmune disease includes:Rheumatoid arthritiss, autoimmunity demyelinating disease are (for example, multiple hard Change, allergic encephalitiss), psoriatic arthritis, endocrine ophthalmopathy, uveoretinitis, systemic lupus erythematosus (sle), weight Disease myasthenia, Graves disease, glomerulonephritiies, autoimmunity hepatic disease, inflammatory bowel (for example, Crohn disease), mistake Quick reaction, allergy, Sjogren syndrome, type i diabetes, primary biliary cirrhosiss, Wegner granulomatosiss, fiber Myalgia, polymyositiss, dermatomyositiss, Multiple Endocrine nonfunction, Schmidt syndrome, Autoimmune uveitis, Ai Di Sick, adrenalitis, thyroiditiss, chronic lymphocytic thyroiditis, autoimmune thyroid disease, pernicious anemia, gastratrophia, Chronic Liver Inflammation, lupoides hepatitis, atherosclerosiss, subacute cutaneous lupus erythema tosuss, hypoparathyroidism, Dresslar are comprehensive Levy, AT, idiopathic thrombocytopenic purpura, hemolytic anemia, pemphigus vulgarises, sky bleb Skin ulcer, dermatitis herpetiformis, alopecia areata (alopecia arcata), pemphigoid, scleroderma, progressive systemic sclerosises, CREST Syndrome (calcinosises, Raynaud phenomenon, esophageal dysmotility, sclerodactyly and telangiectasis), male and female Property autoimmunity is sterile, ankylosing spondylitises, ulcerative colitiss, mixed connective tissue disease, polyarteritis nodosa, be System property necrotizing vasculitis, atopic dermatitiss, atopic rhinitis, Goodpasture's syndrome, chagas disease, sarcoidosises, rheumatism Heat, asthma, recurrent abortion, antiphospholipid syndrome, farmer lung, erythema multiforme, postcardiotomy syndrome, Cushing are comprehensive Disease, ACAH, bird fancier's lung (bird-fancier ' s lung), toxic epidermal's necrosis are molten Solution disease, Alport syndrome, alveolitis, allergic pulmonary alveolitiss, fibrosing alveolitiss, interstitial lung disease, erythema nodosum, bad Cellulitis Pyoderma, transfusion reaction, aortic arch syndrome, polymyalgia rheumatica, temporal arteritiss, schistosomicide, giant cell arteritis, Ascariasis, aspergillosis, Sampter syndrome, eczema, lymphomatoid granulomatosises, Behcet disease, rheumatoid pneumoconiosiss, kawasaki disease, Dengue fever, encephalomyelitiss, endocarditiss, myocardium endocardium fibrosiss, endophthalmitis, persistently grand property rising property erythema, psoriasiss, fetus Erythroblastosis, eosinophilic fasciitiss, eosinophilic fasciitis, Felty syndrome, filaricide, cyclitises, chronic ciliary Body inflammation, heterochronia cyclitises, Fuchs cyclitises, IgA nephropathy, Heng-house purpura, graft versus host disease, transplant rejection, Cardiomyopathy, Yi-orchid syndrome, relapsing polychondritises, cryoglobulinemia, macroglobulinemia Waldenstron, Ai Wen This syndrome and autoimmunity gonadal failure.
In some embodiments, autoimmune disease is the disease of following cell:Disease (for example, the system of bone-marrow-derived lymphocyte Property lupus erythematosus, Goodpasture's syndrome, rheumatoid arthritiss and type i diabetes), the disease (example of Th1- lymphocyte As, rheumatoid arthritiss, multiple sclerosiss, psoriasiss, Sjogren syndrome, chronic lymphocytic thyroiditis, Graves disease, primary Property biliary cirrhosiss, Wegner granulomatosiss, tuberculosis or graft versus host disease) or Th2- lymphocyte disease (example As atopic dermatitiss, systemic lupus erythematosus (sle), atopic asthma, nose conjunctivitis, allergic rhinitis, door syndrome difficult to understand, systematicness Hardening or chronic graft versus host disease).Generally, the disease being related to dendritic cell is related to Th1- lymphocyte or Th2- lymph The disease of cell.In some embodiments, autoimmune disease is the immunological diseases of T cell mediation.
In some embodiments, the amount scope of the conjugate giving is about 0.01 to about 10mg/kg/ dosage.At some In embodiment, the amount scope of the conjugate giving is about 0.01 to about 5mg/kg/ dosage.In some embodiments, give The amount scope of conjugate be about 0.05 to about 5mg/kg/ dosage.In some embodiments, the amount scope of the conjugate giving It is about 0.1 to about 5mg/kg/ dosage.In some embodiments, the amount scope of the conjugate giving is about 0.1 to about 4mg/ Kg/ dosage.In some embodiments, the amount scope of the conjugate giving is about 0.05 to about 3mg/kg/ dosage.Real at some The amount scope applying the conjugate in mode, giving is about 0.1 to about 3mg/kg/ dosage.In some embodiments, the knot giving The amount scope of compound is about 0.1 to about 2mg/kg/ dosage.
Including other forms
Unless otherwise prescribed, well-known ion, salt, solvate and the protection of these substituent groups are hereinbefore included Form.For example, refer to that carboxylic acid (- COOH) also includes its anion (carboxylate radical) form (- COO-), salt or solvate, and Conventional protected forms.Similarly, refer to that amino includes the protonated form (- N of amino+HR1R2), salt or solvate, for example, Hydrochlorate, and the conventional protected forms of amino.Similarly, refer to that hydroxyl also includes its anionic form (- O-), salt or solvent Compound, and conventional protected forms.
Salt
Can be for example, medicinal easily or it is expected that preparation, purification and/or the corresponding salt processing reactive compound Salt.The example of pharmaceutical salts is discussed at Berge, et al., J.Pharm.Sci., 66,1-19 (1977).
For example, if compound is anionic compound, or there is functional group (for example ,-COOH that it can be anion Can be-COO-), then can be with suitable salt forming cation.The example of suitable inorganic cation includes but is not limited to Alkali metal ion such as Na+And K+, alkaline earth metal cation such as Ca2+And Mg2+, and other cationes such as Al+3.Suitable organic sun The example of ion includes but is not limited to ammonium ion (i.e. NH4 +) and replace ammonium ion (such as NH3R+、NH2R2 +、NHR3 +、NR4 +). The example of some substituted ammonium ions being suitable for is the ammonium ion that those replace, and it is derived from:Ethamine, diethylamine, hexanamine, three Ethamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and trometamol (tromethamine), and aminoacid, such as lysine and arginine.The example of common quaternary ammonium ion is N (CH3)4 +.
If compound is cationic compound, or there is the functional group (such as-NH that it can be cation2Can be- NH3 +), then can be with suitable anion forming salt.The example of suitable inorganic anion is including but not limited to derived from following Those of mineral acid:Hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid and phosphorous acid.
The example of suitable organic anion is including but not limited to derived from those of following organic acid:2- acetyloxy phenyl first Acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, ethylenediaminetetraacetic acid, ethane two sulphur Acid, ethyl sulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic, hydroxymaleic acid, hydroxynaphthoic acid, hydroxyl second sulphur Acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, methanesulfonic acid, glactaric acid, Oleic acid, oxalic acid, Palmic acid, flutter acid, pantothenic acid, benzene Acetic acid, benzenesulfonic acid, propanoic acid, acetone acid, salicylic acid, stearic acid, succinic acid, p-aminobenzene sulfonic acid, tartaric acid, toluenesulfonic acid and penta Acid.The example of suitable macromolecule organic anion includes but is not limited to those macromolecule organic anions, and it is derived from following poly- Close acid:Tannic acid, carboxymethyl cellulose.
Solvate
Can easily or desirably prepare, purification and/or process reactive compound coordinative solvent compound.Term " solvate " herein to be used with conventional sense, is used to refer to solute (salt of such as reactive compound, reactive compound) Complex with solvent.If solvent is water, solvate can be conveniently referred to as hydrate, for example, monohydrate, two hydrations Thing, trihydrate etc..
Carbinolamine
The present invention includes wherein crossing the compound of the imine linkage interpolation solvent of (across) PBD part, and it illustrates hereafter, Wherein solvent is water or alcohol (RAOH, wherein RAIt is C1-4Alkyl):
These forms can be referred to as carbinolamine and the methanol amidogen ether form of PBD.The balance of these equatioies depends on finding The condition of compound and the part characteristic of itself.
For example, it is possible to come in solid form to separate these specific compounds by lyophilization.
Isomer
Some compounds can be with one or more specific geometric format, optical form, enantiomeric form, diastereomer Form, epimeric form, dystopy isomeric forms, stereoisomer form, tautomeric forms, conformational forms or different Head isomeric forms, including but not limited to cis and trans;E type and Z-type;C formula, t formula and r formula;Interior form and outer form;R type, S type and meso-form;D type and L-type;D type and l type;(+) and (-) form;Keto-acid, enol form and enolate-forms;Cis and Trans;To oblique formula and anticline form;Alpha form and beta form;Axial form and calm form;Boat form, chair form, torsion formula, envelope type And half-chair;And combinations thereof, hereinafter collectively referred to as " isomer " (or " isomeric forms ").
It should be noted that unless what following article was discussed for tautomeric forms, from term " isomer " (as at this Used in literary composition) clearly exclusion structure (or construction) isomer (that is, its difference is that connection from atom to atom not only exists Isomer in atom position in space).For example, refer to methoxyl group (- OCH3) and be not construed as referring to its structure Isomer (methylol ,-CH2OH).Similarly, refer to Chloro-O-Phenyl and be not construed as referring to its constitutional isomer (m-chloro Phenyl).However, referring to that a class formation can include falling structural isomer forms (the such as C within the scope of the above-mentioned type1-7 Alkyl includes n-pro-pyl and isopropyl;Butyl includes normal-butyl, isobutyl group, sec-butyl and the tert-butyl group;Methoxyphenyl includes neighbour Methoxyphenyl, m-methoxyphenyl and p-methoxyphenyl).
Above-mentioned exclusion is not related to tautomeric forms, such as exists, for example, following tautomer centering:Ketone/enol (as shown below), imines/enamine, amide/imino group alcohol, amidine/amidine, nitroso-group/oxime, thioketone/alkene mercaptan, N- nitroso-group/hydroxyl In base azo and nitro/isonitro for example, keto-acid, enol form and enolate-forms.
It should be noted that term " isomer " is particularly including the compound with one or more isotopes replacements.For example, H can be any isotope form, including1H、2H (D) and3H(T);C can be any isotope form, including12C、13C and14C;O can be any isotope form, including16O and18O;Etc..
Unless otherwise prescribed, refer to that specific compound includes all above-mentioned isomeric forms, including (whole or in part) Their raceme and other mixture.For preparing (such as asymmetric synthesis) and separating (such as fractional crystallization and chromatography side Method) method of above-mentioned isomeric forms is as known in the art, or be readily available in a known way.Wherein pass through to adapt to this Method or known method that culture and education is led.
General synthetic route
In below with reference to document, discussion therein is incorporated into by the extensive discussions synthesis of PBD compound by quoting This:
A) WO00/12508 (page 14 to 30);
B) WO2005/023814 (page 3 to 10);
C) WO2004/043963 (page 28 to 29);And
D) WO2005/085251 (page 30 to 39).
Synthetic route
Can be by the compound of the compound synthesis present invention of formula 2, wherein R10And R11In their nitrogen combined thereon and Form nitrogen-carbon double bond between carbon atom:
Wherein R2、R6、R7、R9、R6’、R7’、R9’、R12, X, X ' and R " be that the compound for Formulas I such as defines, ProtNIt is Nitrogen-protecting group group for synthesis and ProtOIt is the oxygen groups for synthesis protection or amidine/amidine group, wherein pass through standard side Method makes imine linkage deprotection.
The compound producing can be its carbinolamine or methanol amidogen ether form, and it depends on used solvent.For example, If ProtNIt is Troc and ProtOIt is the oxygen blocking group for synthesis, then carry out deprotection to produce using Cd/Pb The compound of formula (I).If ProtNIt is SEM or similar group, and ProtOIt is oxo group, then can be by also original Remove oxo group, this produces shielded carbinolamine intermediate, and then it can be treated to remove SEM blocking group, connects Elimination water.Can be by, for example, four lithium borohydrides, carry out the compound of reduction-type 2, are simultaneously used for removing SEM blocking group Suitable mode is to use silica gel treatment.
R is comprised by coupling12Organometallic derivatives, such as organic boron derivative, can be by the compound synthesis of formula 3a The compound of formula 2:
Wherein R2、R6、R7、R9、R6’、R7’、R9’, X, X ' and R " be that the compound for formula 2 such as defines.Organic boron derives Thing can be borate or boric acid.
R is comprised by coupling2Organometallic derivatives, or its precursor, such as organic boron derivative, can be by the change of formula 3b The compound of compound synthesis type 2:
Wherein R12、R6、R7、R9、R6’、R7’、R9’, X, X ' and R " be that the compound for formula 2 such as defines.Organic boron derives Thing can be borate or boric acid.
R comprised by the about single equivalent (such as 0.9 or 1 to 1.1 or 1.2) of coupling2Or R12Organometallic derivatives, As organic boron derivative, can be by compound synthesis formula 3a of formula 4 and the compound of 3b:
Wherein R2、R6、R7、R9、R6’、R7’、R9’, X, X ' and R " be that the compound for formula 2 such as defines.
By in palladium catalyst such as Pd (PPh3)4、Pd(OCOCH3)2、PdCl2、Pd2(dba)3Carry out under conditions of presence Above-mentioned coupling.Coupling can be carried out at the standard conditions, or coupling can also be carried out under microwave condition.
Generally carry out two Coupling step successively.They can enter in the case of being with or without purification between two steps OK.If not done by purification, then above-mentioned two step can be carried out in same reaction vessel.The second Coupling step with After typically require purification.Column chromatography or ionic energy transfer purifying compound from undesirable by-product can be passed through.
The synthesis of the compound of formula 4, wherein Prot is described in detail in WO00/12508OIt is oxo group and ProtN It is SEM, it is incorporated herein by reference.Particularly, with reference in the scheme 7 of page 24, during wherein above-claimed cpd is designated as Mesosome P.This synthetic method is also described in WO2004/043963.
The synthesis of the compound of formula 4, wherein Prot is described in WO2005/085251OIt is the protection for synthesis Oxygen groups, its synthesis is incorporated herein by reference.
Can be by adding suitable bisulfites or sulfinate, then suitable purification step, by the chemical combination of Formulas I Thing (wherein R10And R11Between the nitrogen that they are combined and carbon atom formed nitrogen-carbon double bond) synthesis Formulas I compound (wherein R10And R10’It is H and R11And R11’It is SOzM),.Further method is described in GB2053894, and it is incorporated herein by reference.
Nitrogen-protecting group group for synthesis
Nitrogen-protecting group group for synthesis is well known in the art.In the present invention, particularly interesting Blocking group is carbamate nitrogen-protecting group group and hemiacetal amine nitrogen blocking group.
Carbamate nitrogen-protecting group group has following structure:
Wherein R '10It is R as defined above.Substantial amounts of suitable group is described in Greene, T.W.and Wuts, G.M.,Protective Groups in Organic Synthesis,3rdEdition,John Wiley&Sons,Inc., 1999 page 503 to 549, it is incorporated herein by reference.
Particularly preferred blocking group includes Troc, Teoc, Fmoc, BOC, Doc, Hoc, TcBOC, 1-Adoc and 2- Adoc.
Other possible groups are nitrobenzyloxycarbonyl (such as 4- nitrobenzyloxycarbonyl) and 2- (phenyl sulfonyl) Ethoxy carbonyl.
It is not preferred with those blocking groups that palladium chtalyst can remove, such as Alloc.
Hemiacetal amine nitrogen blocking group has following structure:
Wherein R '10It is R as defined above.As amide blocking group, substantial amounts of suitable group is described in Greene,T.W.and Wuts,G.M.,Protective Groups in Organic Synthesis,3rdEdition, Page 633 to 647 of John Wiley&Sons, Inc., 1999, it is incorporated herein by reference.Group disclosed herein is permissible For compound used in the present invention.Such group includes but is not limited to SEM, MOM, MTM, MEM, BOM, nitro or methoxy BOM, Cl that base replaces3CCH2OCH2-.
Oxygen groups for the protection of synthesis
Oxygen groups for the protection of synthesis are well known in the art.Substantial amounts of suitable oxygen blocking group description In Greene, T.W.and Wuts, G.M., Protective Groups in Organic Synthesis, 3rdEdition, Page 23 to 200 of John Wiley&Sons, Inc., 1999, it is incorporated herein by reference.
Classification of special interest includes silyl ether, methyl ether, alkyl ether, benzylic ether, ester, acetass, benzoic acid Ester, carbonic ester and sulphonic acid ester.
Preferably oxygen blocking group includes acetass, TBS and THP.
Synthetic drug conjugate
As described earlier, conjugate can be prepared.As in U.S. Patent number US6,214,345 in description, permissible Preparation has dimaleoyl imino (A), peptide group (L1) and certainly eliminate group (L2) joint, it is incorporated herein by reference.As In WO2009/0117531 in description, can prepare with dimaleoyl imino (A) and peptide group (L1) joint, it passes through Quote and be hereby incorporated by.According to list of references cited herein or s known as technical staff, other joints can be prepared.
Linker-drug compound can be prepared according to method as known in the art.Can be according to being generally described in U.S. State's patent No. US6,214,345 and US7, the method in 498,298 and WO2009-0117531, or known to the skilled person Method, to carry out the bonding of the active group of (PDB dimer drug unit) amine X substituent group and connector unit.
As in Doronina et al., Nature Biotechnology, described in 2003,21,778-784, permissible By antibodies in linker-drug compound.Briefly, at 37 DEG C, to be reduced with three (carboxyethyl) phosphonium salt hydrochlorate (TCEP) Antibody (4-5mg/mL) in PBS, above-mentioned PBS comprises 50mM sodium borate (pH7.4).By with 5,5 '-dithio two (2- nitre Yl benzoic acid) the progress to monitor reaction for the reaction, it reduces inter-chain disulfide, then allows to carry out desired until realizing Mercaptan/mAb level.Then the antibody of reduction is cooled to 0 DEG C and with the maleimide agent-linker of 1.5 equivalents/anti- Body mercaptan carrys out alkylation.After 1 hour, be quenched by adding the NAC of 5 equivalents (terminate, Quenched) react.PD-10 post removes the agent-linker through being quenched by gel filtration.Then pass through 0.22 μm to inject Filter carrys out aseptic filtration ADC.By the spectrum analyses at 280nm and 329nm respectively, correct medicine extinction at 280nm The contribution of degree is it may be determined that protein concentration.Size exclusion chromatography may be used to determine the degree of antibody aggregation, and RP- HPLC may be used to determine the level of the agent-linker that remaining NAC- terminates.
As in International Patent Publication WO2008/070593 or as described below, can have half Guang ammonia of introducing In linker-drug compound, it is incorporated into herein the antibodies of sour residue.By adding 10 equivalent TCEP and 1mM EDTA simultaneously With 1M Tris buffer (pH9.0) by pH regulator to 7.4, to reduce the cysteine residues comprising to introduce in heavy chain completely Antibody.After incubating 1 hour at 37 DEG C, reaction is cooled to 22 DEG C and adds the hydroascorbic acid of 30 equivalents to select Reoxidize natural disulphide bonds to property, leave the cysteine of the introducing being in reducing condition simultaneously.With 1M Tris buffer (pH3.7) by pH regulator to 6.5, reaction is then allowed to carry out at 22 DEG C 1 hour.Then pass through to add 1M Tris buffer (pH9.0), the pH of solution is improved again to 7.4.The PBD medicine joint of 3.5 equivalents in DMSO is placed on suitable In container, for being diluted with propylene glycol before adding reaction.In order to keep the solubility of PBD medicine joint, first with the third two The ultimate density that alcohol dilutes antibody itself to 33% (for example, if antibody-solutions are in 60mL reaction volume, adds 30mL Propylene glycol).The propylene glycol (in this embodiment for 30mL) of same volume is added PBD medicine joint as diluent.Mixed After conjunction, solution in propylene glycol for the PBD medicine joint is added antibody-solutions to realize combining;The ultimate density of propylene glycol is 50%.Allow reaction to carry out 30 minutes, be then quenched by adding the NAC of 5 equivalents.By means of The ultrafiltration of 30kD film carrys out purification ADC.(it should be noted that for any specific PBD, third being used in the reaction can be reduced The concentration of glycol, this is because its sole purpose is to maintain solubility in aqueous medium for the medicine joint.)
For the linker-drug compound of halogen-ethanamide, combination generally can be carried out as follows.To reduction and oxygen again The antibody (having the cysteine having been introduced in heavy chain) changed is in 10mM Tris (pH7.4), 50mM NaCl and 2mM DTPA In solution, add 0.5 volume propylene glycol.And then, before combination, the linker-drug compound preparing ethanamide exists 10mM solution in dimethyl acetylamide.By with add antibody-solutions equivalent propylene glycol add 6 times of molar excess joint- Medical compoundss.Linker-drug solution will be diluted add antibody-solutions and use 1M Tris (pH9) by pH regulator to 8-8.5. Allow to be combined reaction 45 minutes at 37 DEG C.Chromatograph to confirm to combine by reduction and the anti-phase PLRP-S of degeneration.With Quadrasil MP resin is removing excessive linker-drug compound, and the use of PD-10 desalting column is 10mM by buffer-exchanged Tris (pH7.4), 50mM NaCl and 5% propylene glycol.
Illustrative synthetic schemes for medicine joint
Below scheme illustrates the route for synthetic drug joint, and the PBD dimer that there is shown with has specified substituent, Link with dimer, but within the scope of the invention, these can be change.
Option A
Glucuronic acid joint intermediate S1 can be processed with surpalite (with reference to literary composition at -78 DEG C in dichloromethane Offer:Jeffrey et al., Bioconjugate Chemistry, 2006,17,831-840) to provide glucuronic acid chloromethane Acid esters, then it pass through to be added dropwise over and be dissolved in CH2Cl2In PBD dimer S2 reaction.Temperature reaction to 0 DEG C through 2 hours, Then extract, compound S3 will be produced.Process S3 with lithium hydroxide monohydrate and (be cooled to 0 in MeOH, oxolane and water DEG C) equal solvent mixture in solution 4 hours, then react with glacial acetic acid, compound S4 will be produced.By maleimide AminocaProyl NHS ester adds solution in DMF for the S4, is subsequently added into diisopropylethylamine, and in room temperature and stirred under nitrogen 2 Hour, desired medicine joint S5 will be produced.
Option b
In the presence of the EEDQ in anhydrous methylene chloride, can (it can be by making horse by maleimide joint S6 Carry out acylimino caproyl N-hydroxy-succinamide and H-Val-Ala-OH react and to synthesize) it is connected to exemplary compounds S2.
Scheme C
In the presence of the EEDQ in 5% ethanol/methylene, joint S8 can be connected to exemplary compounds, S2. By means of using Ph3P, pyrrolidine and four palladiums (in anhydrous methylene chloride), can carry out the deprotection of S9.Having in DMF In the presence of DIPEA, by adding maleimidocaproyl-NHS ester, S10 can be changed into desired product.
Further preference
Following preference goes for all aspects of the invention (as described above), or can be related to single aspect.Can Preference to be combined together with any combinations.
In some embodiments, R6’、R7’、R9’、R10’、R11’And Y ' preferably respectively with R6、R7、R9、R10、R11With Y phase With.
Dimer links
Y and Y ' is preferably O.
R " is suitably without the C of substituent group3-7Alkylidene.It is highly preferred that R " it is C3、C5Or C7Alkylidene.Most preferably, R " It is C3Or C5Alkylidene.
R6To R9
R9Preferably H.
R6It is preferably selected from H, OH, OR, SH, NH2, nitro and halogen, and more preferably H or halogen, and most preferably H.
R7It is preferably selected from H, OH, OR, SH, SR, NH2, NHR, NRR ' and halogen, and be more preferably independently selected from H, OH and OR, wherein R are preferably selected from optionally substituted C1-7Alkyl, C3-10Heterocyclic radical and C5-10Aryl.R can more preferably can or not The C that can be substituted1-4Alkyl.Substituent group interested is C5-6Aryl (such as phenyl).Particularly preferred at 7 positions takes Dai Ji is OMe and OCH2Ph.Other particularly interesting substituent groups are dimethylamino (i.e. NMe2);-(OC2H4)qOMe, Wherein q is 0 to 2;Nitrogenous C6Heterocyclic radical, including morpholino, piperidyl and N- methyl-piperazinyl group.
These preference are respectively suitable for R9’、R6’And R7’.
R2
RC1、RC2And RC3Independently selected from H and unsubstituted C1-2Alkyl.Some preferred embodiment in, RC1、RC2 And RC3It is all H.In other embodiments, RC1、RC2And RC3It is all methyl.In some embodiments, RC1、RC2And RC3Independent Ground is selected from H and methyl.
X is the group being listed below selected from inclusion:OH、SH、CO2H, COH, N=C=O, NHNH2、CONHNH2And NHRN, wherein RNIt is selected from and include H and C1-4The group of alkyl.X preferably be OH, SH, CO2H ,-N=C=O or NHRN, and can be more preferably:OH、SH、CO2H ,-N=C=O or NH2.Particularly preferred group Including:OH, SH and NH2, wherein NH2It is most preferred group.
R12
R12It is selected from:
(a)C5-10Aryl, is alternatively replaced by selected from the one or more substituent groups including following group:Halogen, nitro, Cyano group, ether, C1-7Alkyl, C3-7Heterocyclic radical and double-epoxide-C1-3Alkylidene;
(b)C1-5Radical of saturated aliphatic alkyl;
(c)C3-6Saturated cyclic alkyls;
(d)Wherein R21、R22And R23It is each independently selected from H, C1-3Saturated alkyl, C2-3Alkenyl, C2-3 Alkynyl and cyclopropyl, wherein in R12In group, the sum of carbon atom is not more than 5;
(e)Wherein R25aAnd R25bOne of be H and another is selected from:(it is by selected from halogen to phenyl Acute pyogenic infection of nails base, methoxyl group group optionally substituted);Pyridine radicals;And thiophenyl;And
(f)Wherein R24It is selected from:H;C1-3Saturated alkyl;C2-3Alkenyl;C2-3Alkynyl;Cyclopropyl;Phenyl (it is optionally substituted by the group selected from halogenated methyl, methoxyl group);Pyridine radicals;And thiophenyl.
Work as R12It is C5-10During aryl, it can be C5-7Aryl.C5-7Aryl can be phenyl or C5-7Heteroaryl, such as furan Mutter base, thiophenyl and pyridine radicals.In some embodiments, R12Preferably phenyl.In other embodiments, R12Preferably Thiophenyl, for example, thiophene -2- base and thiene-3-yl.
Work as R12It is C5-10During aryl, it can be C8-10Aryl, such as quinolyl or isoquinolyl.Quinolyl or isoquinolin Base can be incorporated into PBD core by any available ring position.For example, quinolyl can be quinoline -2- base, quinoline -3- base, Quinolyl-4, quinoline -5- base, quinoline -6- base, quinoline -7- base and quinoline-8-yl.Wherein, quinoline -3- base and quinoline -6- base Can be preferred.Isoquinolyl can be isoquinolyl-1, isoquinolin -3- base, isoquinolin -4- base, isoquinolin -5- base, different Quinoline -6- base, isoquinolin -7- base and isoquinolin -8- base.Wherein, isoquinolin -3- base and isoquinolin -6- base can be preferred.
Work as R12It is C5-10During aryl, it can carry any amount of substituent group.It preferably carries 1 to 3 substituent group, its In 1 and 2 substituent group be more preferred, and mono-substituted group is most preferred.Substituent group can be in any position.
In R12It is C5-7In the case of aryl, monosubstituted base be preferably on annular atom, its not adjacent to compound The key of remainder, i.e. it is preferably β the or γ position with the key of the remainder of compound.Therefore, in C5-7Aryl is phenyl In the case of, substituent group is preferably in meta or para position, and more preferably in para-position.
In R12It is C8-10In the case of aryl, such as quinolyl or isoquinolyl, it can be in quinoline or isoquinolin ring Any amount of substituent group is carried at any position.In some embodiments, it carries one, two or three substituent group, And these substituent groups can be on nearside or distal loop or both (if more than one substituent group).
R12Substituent group, works as R12It is C5-10During aryl
Work as R12It is C5-10During aryl, if in R12On substituent group be halogen, then its preferably F or Cl, more preferably F.
Work as R12It is C5-10During aryl, if in R12On substituent group be ether, then it can be alkane in some embodiments Epoxide, for example, C1-7Alkoxyl (such as methoxyl group, ethyoxyl), or it can be C in some embodiments5-7Aryloxy group (example As phenoxy group, pyridyloxy, furan epoxide).Alkoxyl itself can be substituted further, such as by amino (such as dimethyl Amino).
Work as R12It is C5-10During aryl, if in R12On substituent group be C1-7Alkyl, it can be preferably C1-4Alkyl is (for example Methyl, ethyl, propyl group, butyl).
Work as R12It is C5-10During aryl, if in R12On substituent group be C3-7Heterocyclic radical, then it can in some embodiments To be C6Nitrogen heterocycle, such as morpholino, thiomorpholine generation, piperidyl, piperazinyl.These groups can be tied via nitrogen-atoms Remainder together in PBD part.These groups can be substituted further, for example, by C1-4Alkyl.If C6Nitrogen heterocyclic ring Base is piperazinyl, then described further substituent group can be on the second nitrogen ring atom.
Work as R12It is C5-10During aryl, if in R12On substituent group be double-epoxide-C1-3Alkylidene, this is preferably double-oxygen Base-methylene or double-epoxide-ethylidene.
Work as R12It is C5-10During aryl, particularly preferred substituent group include methoxyl group, ethyoxyl, fluorine-based, chloro, cyano group, double- Epoxide-methylene, methyl-piperazinyl group, morpholino and methyl-phenylsulfanyl.For R12Another particularly preferred substituent group be two Methylamino propoxyl group.
Work as R12It is C5-10During aryl, particularly preferred substituted R12Group includes but is not limited to:4- methoxyl group-phenyl, 3- Methoxyphenyl, 4- aminomethyl phenyl, 4- ethyoxyl-phenyl, 3- ethyoxyl-phenyl, 4- fluoro-phenyl, the chloro- phenyl of 4-, 3,4- bis- Oxymethylene-phenyl, 4- methylphenyl-sulfanyl, 4- cyano-phenyl, 4- Phenoxyphenyl, quinoline -3- base and quinoline -6- base, isoquinoline Quinoline -3- base and isoquinolin -6- base, 2- thienyl, 2- furyl, methoxyl group naphthyl and naphthyl.Alternatively possible substituted R12 Group is 4- nitrobenzophenone.
Work as R12It is C1-5During radical of saturated aliphatic alkyl, it can be methyl, ethyl, propyl group, butyl or amyl group.In some enforcements In mode, it can be methyl, ethyl or propyl group (n-pentyl or isopropyl).In some of these embodiments, it is permissible It is methyl.In other embodiments, it can be butyl or amyl group, and it can be straight or branched.
Work as R12It is C3-6During saturated cyclic alkyls, it can be cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.In some enforcements In mode, it can be cyclopropyl.
Work as R12It isWhen, R21、R22And R23It is each independently selected from H, C1-3Saturated alkyl, C2-3Alkenyl, C2-3Alkynyl and cyclopropyl, wherein in R12The sum of the carbon atom in group is not more than 5.In some embodiments, in R12Base The sum of the carbon atom in group is not more than 4 or no more than 3.
In some embodiments, R21、R22And R23One of be H, and other two kinds of groups be selected from H, C1-3Saturation alkane Base, C2-3Alkenyl, C2-3Alkynyl and cyclopropyl.
In other embodiments, R21、R22And R23In two kinds be H, and a kind of other groups be selected from H, C1-3Saturation alkane Base, C2-3Alkenyl, C2-3Alkynyl and cyclopropyl.
In some embodiments, it is not the group of H selected from methyl and ethyl.In some of these embodiments, no Be the group of H be methyl.
In some embodiments, R21It is hydrogen.
In some embodiments, R22It is hydrogen.
In some embodiments, R23It is hydrogen.
In some embodiments, R21And R22It is H.
In some embodiments, R21And R23It is H.
In some embodiments, R22And R23It is H.
Particularly interesting R12Group is:
Work as R12It isWhen, R25aAnd R25bOne of be hydrogen, and another is selected from:(it is by being selected to phenyl Halogen, methyl, methoxyl group group optionally substituted);Pyridine radicals;And thiophenyl.In some embodiments, be not H base Group is optionally substituted phenyl.If the optional substituent group of phenyl is halogen, it is preferably fluorine.In some embodiments, Phenyl is unsubstituted.
Work as R12It isWhen, R24It is selected from:H;C1-3Saturated alkyl;C2-3Alkenyl;C2-3Alkynyl;Cyclopropyl;Phenyl (it is optionally substituted by the group selected from halogenated methyl, methoxyl group);Pyridine radicals;And thiophenyl.If phenyl is optional Substituent group is halogen, then it is preferably fluorine.In some embodiments, phenyl is unsubstituted.
In some embodiments, R24Selected from H, methyl, ethyl, vinyl and acetenyl.In these embodiments one In a little, R24Selected from H and methyl.
M and z
Preferably, M and M ' is univalent medicinal cation, and is more preferably Na+.
Z is preferably 3.
The particularly preferred compound of the present invention has Formulas I a:
Wherein
N is 1 or 3;
R1aIt is methyl or phenyl;
R12aIt is selected from:
(a)
(b)
(c)
(d)
(e)
(f)
For R12aFurther group can be:
(g)And
(h)
The third aspect
In the appropriate case, the preference above with respect to first aspect description goes for compound in this respect.
Work as R10When being carbamate nitrogen-protecting group group, it can be preferably Teoc, Fmoc and Troc, and can be more excellent Selection of land is Troc.
Work as R11It is O-ProtOWhen, wherein ProtOIt is oxygen blocking group, ProtOMay be preferred that TBS or THP, and permissible More preferably TBS.
Work as R10When being hemiacetal amine nitrogen blocking group, it can be preferably MOM, BOM or SEM, and can be more preferably It is SEM.
Depend on the circumstances, the preference for the compound of Formulas I is applied to the D of a sixth aspect of the present invention.For example, Six aspects, PBD dimer can be any compound or its pharmaceutical salts or the solvate (described herein) of Formulas I, and expectedQuiltSubstitute,QuiltSubstitute, andQuiltSubstitute, wherein wavy line represents the junction point with connector unit.
Therefore, the conjugate of the present invention includes those and has with the conjugate of following formula (IV)
L-(LU-D)p(IV)
Or its pharmaceutical salts or solvate, wherein L is part unit (that is, targeting agent), and LU is connector unit and PBD bis- Aggressiveness D D is any compound of Formulas I, or its pharmaceutical salts or solvate (described herein), and expected, QuiltSubstitute,QuiltSubstitute, andQuiltSubstitute, wherein wavy line represents the junction point with connector unit.
A the conjugate of () present invention includes, for example, with those of the formula conjugate:
CBA–A1–L1–*
Wherein asterisk represents the junction point with PBD dimer (D), and CBA is cell binding agent, L1It is specificity unit, lead to Cross the effect of enzyme, it is cleavable, and A1It is by L1It is connected to the extension unit of cell binding agent.
B the conjugate of () present invention includes, for example, with those of the formula conjugate:
CBA–A1–L1–*
Wherein asterisk represents the junction point with PBD dimer (D), and CBA is cell binding agent, A1It is by L1It is connected to cell The extension unit of bonding agent, L1It is specificity unit, by the effect of cathepsin, it is cleavable;L1It is dipeptides; L1It is dipeptides, by the effect of cathepsin, it is cleavable;Or L1It is to be selected from-Phe-Lys- ,-Val-Ala- ,-Val- The dipeptides of Lys- ,-Ala-Lys- and-Val-Cit-.
The present invention includes in (a) and any conjugate described in (b), wherein A preferably in combination with thing1It is
Wherein asterisk represents and L1Junction point, wavy line represents the junction point with CBA, and n is 0 to 6 (preferably n It is 5).
Embodiment
For implementing the general experimental technique of row 1
In ADP220 polariscope (Bellingham Stanley Ltd.) upper measurement optical activity and in units of g/100mL To provide concentration (c).Measure fusing point using numeral melting point instrument (Electrothermal).Use Perkin-Elmer Spectrum1000FT IR spectrometer come to record IR spectrum.At 300k, using Bruker Avance NMR spectrometer, exist respectively Obtain at 400 and 100MHz1H and13C H NMR spectroscopy.Report chemical shift with respect to TMS (δ=0.0ppm), and signal designation is S (unimodal), d (bimodal), t (triplet), dt (double triplet), dd (bimodal is bimodal), ddd (bimodal double doublet) or m are (many Weight peak), wherein coupling constant is provided for unit with hertz (Hz).Have Waters2996PDA's using being connected to Waters Micromass ZQ instrument on Waters2695HPLC is collecting mass spectrum (MS) data.The Waters using Micromass ZQ parameter is:Capillary pressure (kV), 3.38;Cone (V), 35;Extractor (V), 3.0;Source temperature (DEG C), 100; Desolvation temperature (DEG C), 200;Cone flow velocity (L/h), 50;Desolvation flow velocity (L/h), 250.Boron using metal coating Silica glass tip, to introduce the sample into instrument, records high score with positive W pattern on Waters Micromass QTOF Global Resolution mass spectrum (HRMS) data.In silica gel aluminium sheet (Merck60, F254) on carry out thin layer chromatography (TLC), and utilize silica gel (Merck60,230-400 mesh ASTM) is carrying out flash chromatography.Except HOBt (NovaBiochem) and supported reagents (Argonaut), outside, every other chemicals and solvent are purchased from Sigma-Aldrich being used without into as supply The purification of step.Under conditions of with the presence of suitable desiccant, under a dry nitrogen atmosphere, anhydrous solvent is prepared by distillation, And be stored inOn molecular sieve or sodium wire.Petroleum ether refers to the fraction of boiling at 40-60 DEG C.
As (it is incorporated herein by reference) synthesis compound 1 described in WO2010/043880 (compound 17).
General LC/MS condition:Mobile phase using water (A) (formic acid 0.1%) and acetonitrile (B) (formic acid 0.1%) is run HPLC(Waters Alliance2695).Gradient:Initial composition 5%B, continues 1.0 minutes, and then, in 3 minutes, 5%B arrives 95%B.Above-mentioned composition is maintained at 95%B lower 0.5 minute, then in 0.3 minute, returns to 5%B.Total gradient run time etc. In 5 minutes.Via zero dead volume T-shaped pipe, (it is passed through mass spectrograph) is separating flow velocity 3.0mL/ minute, 400 μ L.Wavelength detecting model Enclose:220 to 400nm.Function type:Diode array (535 scanning).Post:Onyx Monolithic C1850x4.60mm.
Synthesis borate
(a) methyl -propyl- 2- ynyl-carbamic acid 2,2,2- thchloro-ethyl ester (I2)
At -78 DEG C, will be molten in DCM (100mL) for Troc chloro-formate (10.2mL, 75.8mmol, 1.05 equivalent) Liquid is added dropwise over N- methyl-propargyl amine (I1) (5g, 72.3mmol, 1 equivalent) and TEA, and (12.08mL, 0.86mmol, 1.2 work as Amount) solution in DCM (150mL).At room temperature it is allowed to reactant mixture returns to is stirred overnight.With water (200mL), 0.1N Aqueous citric acid solution (200mL), saturated aqueous NaHCO3 (100mL) and saline (50mL) wash solution.With magnesium sulfate come drying Organic faciess, are then evaporated in vacuo to provide desired product, as water white oil (15.5g, 93%).Not over LC/MS inspection Survey.1H NMR(400MHz,CDCl3) δ 4.69 (s, 2H), 4.09 (d, 2H, J=2.4Hz), 3.01-2.97 (m, 3H), 2.20 (t, 1H, J=2.4Hz).
(b) methyl-[(E) -3- (4,4,5,5- tetramethyl-[1,3,2] dioxaborinate -2- base)-pi-allyl]-amino first Sour 2,2,2- trichloro ethyl ester (I3)
Under 0 DEG C and argon, by pure (neat) BH3.SMe2Complex (1.7mL, 16.8mmol, 1.3 equivalent) is added dropwise over α (-) solution in anhydrous THF (5mL) for the pinene (5.4mL, 33.6mmol, 2.6 equivalent).Stirring reaction is allowed overnight and to observe To white depositions.At 0 DEG C, the methyl-propargyl amine (3g, 13mmol, 1 equivalent) that Troc is protected is at anhydrous THF (5mL) In solution add reactant mixture, and allow to carry out at room temperature reacting overnight.Then add at 0 DEG C pure acetaldehyde (22mL, 387mmol, 30 equivalents) and stirring mixture 5 hours.Removing volatiles under vacuum.Add ether (20mL), then where add frequency Alcohol (2.4g, 20.1mmol, 1.2 equivalent).Allow mixture to be stirred at room temperature overnight.Mixing is absorbed in pentane (20mL) Thing, is washed with water (2x10mL), then dried over magnesium sulfate.Remove volatile matter by rotary evaporation and pass through flash chromatography (gradient:0/100 to 10/90 ethyl acetate/hexane v/v) carry out purification residue.Visualize pure fraction quilt with potassium permanganate Pull to produce the pure borate of 2.25g (46%).Not over LC/MS detection.1H NMR(400MHz,CDCl3)δ6.44(dt, 1H, J=18.0Hz, J=4.9Hz), 5.48 (dd, 1H, J=18.0Hz, J=1.3Hz), 4.66 (d, 2H, J=6.3Hz), 3.95 (dd, 2H, J=4.9Hz, J=1.7Hz), 2.89 (d, 2H, J=8.5Hz), 1.20 (s, 12H).
Embodiment 1
(a) compound 2
Compound 1 (compound 17 of WO2010/0043880) is dissolved in anhydrous THF (25mL) and cold at -78 DEG C But (700mg, 0.65mmol, 1 equivalent).Solution (1M, 1.95mL, 1.95mmol, 3 equivalent) in THF for the super hydride is delayed Slow injection enters the reactant mixture of stirring.After 30 minutes, observe that reaction completes.With water (10mL) be quenched reactant mixture with DCM (100mL) is used to extract afterwards.With water (100mL), then wash Organic substance with saline (50mL).To be dried organic through magnesium sulfate Phase, then by rotary evaporation, then high vacuum removes volatile matter.With DCM (50mL), ethanol (140mL), water (70mL) Process residue with silica gel (100g).At room temperature it is allowed to stir cementitious mixtures 3 days.Mixed by slow filtration of sinter funnel Compound, then to wash silicon residue with 90/10 chloroform/methanol v/v (500mL).Washed with water (300mL), saline (100mL) Organic faciess, are dried (magnesium sulfate), filter, are then evaporated in vacuo, and to provide crude material, it passes through flash chromatography (gradient, first Alcohol/chloroform, 0/100 to 2.5/97.5, v/v) purification to be to produce the mono- trifluoromethanesulfonic acid of the relatively unstable PBD of 150mg (29%) Ester (mono triflate) (2), it is directly used in next step.
(b) compound 3
At room temperature, by solid Pd (PPh3)4(6.6mg, 5.7 μm of ol) addition mono- triflate of PBD (2) (150mg, 0.19mmol) and Troc protection boronation ester (boronated ester) (I3) (114mg, 0.31mmol) toluene (8mL), EtOH (4mL) and Na2CO3(65mg, 0.61mmol) is (in H2In O (4mL)) in agitating solution.Under nitrogen atmosphere it is allowed to stir Reactant mixture 20 hours, at this time, it is believed that reaction is completed, as judged by LC/MS and TLC (EtOAc).In vacuum decompression Under solvent is removed by rotary evaporation, then in EtOAc (30mL) and H2The residue of generation is distributed between O (60mL).With EtOAc (2x30mL) is extracting aqueous phase and to use H2O (30mL), saline (40mL), to wash the organic layer of merging, are dried (MgSO4), Filter and evaporate, to provide crude product (3).By flash chromatography (gradient, methanol/chloroform, 0.5/100 to 2.5/97.5, v/v) Carry out purification of crude product, to produce 60mg (35.5%).3.28 minutes m/z (879.97) M+H of LC/MS room temperature.
(c) compound 4
By subdivision fresh preparation Cd/Pb to (150mg) add Troc protection PBD dimer (3) (55mg, 0.070mmol) the solution in THF/1N aqueous acetic acid ammonium (1.5mL/1.5mL).It is stirred vigorously reactant mixture and at 1 hour Observe later and complete.Filtering mixt is come and by filtrate absorption in the 15%MeOH in chloroform by Celite (celite) In (v/v, 3x20mL) and 1N aqueous carbonic acid sodium (50mL).To wash Organic substance with saline (20mL), dried over sodium sulfate, so Removing volatiles under vacuum afterwards.There is provided compound 4 by preparing LC/MS come purification of crude material.2.43 points of LC/MS room temperature Clock m/z (704.4) M+H.
General experimental technique for following examples
Using the Agilent1200 series LC/MS with the quadrupole MS of Agilent6110, obtained with electrospray ionization LCMS data.0.1% acetic acid in water for the mobile phase A.Mobile phase B in acetonitrile 0.1%.Flow velocity is 1.00ml/ minute. Gradient is to rise to 95%B through 3 minutes from 5%B, is maintained at 95%B lower 1 minute, then fell back to 5%B through 6 seconds.Total operation Time is 5 minutes.Post:Gemini-NX3 μm of C18 of Phenomenex, 30x2.00mm.Based on the UV detection at 254nm Tomographic map.To obtain mass spectrum using MS and with cation mode (positive mode).Used with 400MHz based on δ yardstick Bruker AV400, to measure proton nmr chemical shift value.Employ following abbreviation:S, unimodal;D, bimodal;T, triple Peak;Q, quartet;M, multiplet;Br, wide.To report coupling constant in units of Hz.Unless otherwise stated, use Merck Kieselgel Silicon stone (Art.9385) carries out column chromatography (by fast procedure).Separated in Waters2795HPLC using coupling The Waters Micromass LCT instrument of module is gathering mass spectrography (MS) data.With silica gel aluminium sheet (Merck60, F254) enter Row thin layer chromatography (TLC).Every other chemicals and solvent be purchased from Sigma-Aldrich or Fisher Scientific and It is used without further purification as supply.
To measure optical rotation (Optical rotation) with ADP220 polariscope (Bellingham Stanley Ltd.) And to provide concentration (c) in units of g/100mL.To measure fusing point using numeral melting point instrument (Electrothermal).With Perkin-Elmer Spectrum1000FT IR spectrometer come to record IR spectrum.At 300k using Bruker Avance NMR Spectrometer, obtains respectively at 400 and 100MHz1H and13C H NMR spectroscopy.To report chemical potential with respect to TMS (δ=0.0ppm) Move, and signal is designated as s (unimodal), d (bimodal), t (triplet), dt (double triplet), dd (bimodal is bimodal), ddd (bimodal double doublet) or m (multiplet), and coupling constant is provided for unit with hertz (Hz).Using coupling in having The Waters MicromassZQ instrument of the Waters2695HPLC of Waters2996PDA is gathering mass spectrography (MS) data.Make Waters Micromass ZQ parameter is:Capillary pressure (kV), 3.38;Cone (V), 35;Extractor (V), 3.0;Source temperature Degree (DEG C), 100;Desolvation temperature (DEG C), 200;Cone flow rate (L/h), 50;Desolvation flow velocity (L/h), 250.With Waters Micromass QTOF Global simultaneously to record high resolution mass spec method (HRMS) data with cation W pattern, its The middle Pyrex tip using metal coating introduces the sample into instrument.With silica gel aluminium sheet (Merck60, F254) carry out thin layer Chromatography (TLC), and to carry out flash chromatography with silica gel (Merck60,230-400 mesh ASTM).Except HOBt (NovaBiochem) Outside supported reagents (Argonaut), every other chemicals and solvent are purchased from Sigma-Aldrich and as supply It is used without further purification.Under a dry nitrogen atmosphere, under conditions of with the presence of suitable desiccant, come by distillation Prepare anhydrous solvent, andStore on molecular sieve or sodium wire.Petroleum ether refers to the fraction of boiling at 40-60 DEG C.
General LC/MS condition:Mobile phase using water (A) (formic acid 0.1%) and acetonitrile (B) (formic acid 0.1%) is run HPLC(Waters Alliance2695).Gradient:Initial Composition 5%B, through 1.0 minutes, then 5%B to 95% in 3 minutes B.Under 95%B, keep composition 0.5 minute, originally in 0.3 minute, return to 5%B.Total gradient run time is equal to 5 minutes. Flow velocity is 3.0mL/ minute, to separate 400 μ L via zero dead volume T-shaped pipe, it is passed into mass spectrograph.Wavelength detection range:220 To 400nm.Function type:Diode array (535 scanning).Post:Onyx Monolithic C1850x4.60mm.
Synthesis key intermediate
(i) 1,1 '-[[(propane -1,3- diyl) two epoxides] double (11aS) -7- methoxyl group -2- [[(trifluoromethyl) sulphonyl Base] epoxide] -10- ((2- (trimethyl silyl) ethyoxyl) methyl) -1,10,11,11a- tetrahydrochysene -5H- pyrrolo- [2,1- C] [1,4]-benzodiazepine- 5,11- diketone (7)
Synthesis compound 5, is such as described in WO2010/043880 (compound 6a), it is incorporated herein by reference.
(a) 1,1 '-[[(propane -1,3- diyl) two epoxides] double [(11aS) -11- sulfo group -7- methoxyl group -2- oxygen -10- ((2- (trimethyl silyl) ethyoxyl) methyl) 1,2,3,10,11,11a- hexahydro -5H- pyrrolo- [2,1-c] [1,4] benzene And diaza- 5,11- diketone]] (6)
Under a nitrogen, by glycol 5 (25.60g, 29.9mmol, 1.0 equivalent), NaOAc, (6.90g, 84.1mmol, 2.8 work as Amount) and TEMPO (0.188g, 1.2mmol, 0.04 equivalent) be dissolved in DCM (326mL).It is cooled to -8 DEG C and through 20 minutes TCCA (9.70g, 41.7mmol, 1.4 equivalent) is added batch-wise, solution becomes dark brown therebetween, and it brightens when reaction is carried out.? After 30 minutes, add cold DCM (200mL) and by Celite come filtering mixt, then use the sodium bicarbonate of saturation/thio Metabisulfite solution (1:1v/v;200mL x2) washing.Through MgSO4Organic layer is dried, filters under reduced pressure and concentrate to produce Diketone 6, is yellow/orange sponge (25.5g, 100%).LC/MS (3.173 minutes (ES+)).m/z:854.20[M]+.1H NMR (400MHz,CDCl3) δ 7.32 (s, 2H), 7.25 (s, 2H), 5.50 (d, 2H, J=10.1Hz), 4.75 (d, 2H, J= 10.1Hz), 4.60 (dd, 2H, J=9.9,3.1Hz), 4.31 4.18 (m, 6H), 3.89 3.84 (m, 8H), 3.78 3.62 (m, 4H), 3.55 (dd, 2H, J=19.3,3.0Hz), 2.76 (dd, 2H, J=18.6,10.2Hz), 2.42 (p, 2H, J=5.8Hz), 0.98–0.91(m,4H),0.00(s,18H).
(b) 1,1 '-[[(propane -1,3- diyl) two epoxides] double (11aS) -7- methoxyl group -2- [[(trifluoromethyl) sulphonyl Base] epoxide] -10- ((2- (trimethyl silyl) ethyoxyl) methyl) -1,10,11,11a- tetrahydrochysene -5H- pyrrolo- [2,1- C] [1,4]-benzodiazepine- 5,11- diketone] (7)
Under -45 DEG C (dry ice/acetonitrile) and under nitrogen atmosphere, with 1 part by anhydrous 2,6- lutidines (1.984g, 17.864mmol, 6.22 equivalents) injection diketone 6 (2.45g, 2.977mmol, 1.0 equivalent) is violent in anhydrous DCM (90mL) Agitating solution.Quick dropwise injection take from the ampoule just opened anhydrous Trifluoromethanesulfonic anhydride (5.04g, 17.86mmol, 6.0 equivalents), not higher than -40 DEG C of keeping temperature simultaneously.Allow stirring reaction mixture 1 hour at -45 DEG C, now TLC (50/ 50v/v normal hexane/EtOAc) and LCMS show parent material consumption completely.Dilute cold reaction mixing with DCM (100mL) immediately Thing, then under being aggressively shaken, with water (1x50mL), 5% citric acid solution (1x100mL), saturation NaHCO3(100mL), salt Water (50mL) washs, through MgSO4Be dried, filtered and concentrated (under reduced pressure) to produce crude product, by flash chromatography (silica gel, Gradient elution 90:10 normal hexane/EtOAc v/v to 60:40 normal hexane/EtOAc v/v) to its purification, to provide diene alcohol three Fluorine methanesulfonates 7, is yellow foam (2.097g, 63%).LC/MS (3.916 minutes (ES+)).m/z:1117.24[M]+ .1H NMR(400MHz,CDCl3) δ 7.33 (s, 2H), 7.26 (s, 2H), 7.14 (t, 2H, J=2.0Hz), 5.51 (d, 2H, J= 10.1Hz), 4.76 (d, 2H, J=10.1Hz), 4.62 (dd, 2H, J=11.0,3.6Hz), 4.32 4.23 (m, 4H), 3.94 3.90 (m, 8H), 3.81 3.64 (m, 4H), 3.16 (ddd, 2H, J=16.4,11.1,2.3Hz), 2.43 (p, 2H, J= 5.9Hz),1.23–0.92(m,4H),0.02(s,18H).
(ii) (E)-(9H- fluorenes -9- base) methyl 3- (4,4,5,5- tetramethyl -1,3,2- dioxaborinate -2- base) allyl Aminocarbamic acid ester (10)
(a) (9H- fluorenes -9- base) methyl propyl- 2- alkynylamino formic acid esters (9)
At -78 DEG C, by solution in DCM (150mL) for the Fmoc chloride (25.00g, 96.64mmol, 1.05 equivalent) It is added dropwise over propargyl amine 8 (5.89mL, 92.04mmol, 1.0 equivalent) and triethylamine (15.4mL, 110.4mmol, 1.2 equivalent) Solution in DCM (200mL).Allow stirring reaction mixture at room temperature, and after 16 hours, with water (300mL), 0.1N aqueous citric acid (300mL), saturated aqueous NaHCO3(300mL) with saline (200mL) wash solution.To do through magnesium sulfate Dry organic faciess, filter and concentrate (under reduced pressure) to provide amorphous white powder.Carry out ultrasonic place in cold hexane (200mL) Reason, then filters to provide product, is white solid (24.316g, 95%).LC/MS (2.758 minutes (ES+)).m/z: 300.0[M+Na]+.1H NMR(400MHz,CDCl3), δ 7.74 (d, 2H, J=7.6Hz), 7.57 (d, 2H, J=7.4Hz), 7.41 7.37 (m, 2H), 7.30 (dt, 2H, J=7.5,1.2Hz), 4.93 (br s, 1H), 4.41 (d, 2H, J=6.9Hz), 4.21 (t, 1H, J=6.4Hz), 3.99 (d, 2H, J=3.3Hz), 2.24 (t, 1H, J=2.5Hz).
(b) (E)-(9H- fluorenes -9- base) methyl 3- (4,4,5,5- tetramethyl -1,3,2- dioxaborinate -2- base) pi-allyl Carbamate (10)
At 0 DEG C with a nitrogen, by pure BH3.SMe2Complex (9.35mL, 92.47mmol, 1.3 equivalent) is added dropwise over α Solution in anhydrous THF (40mL) for (-) pinene (25.20g, 19.72mmol, 2.6 equivalent).Stirring reaction is allowed overnight and to see Observe white depositions.At 0 DEG C, by Fmoc propargyl amine 9 (19.72g, 71.13mmol, 1.0 equivalent) in anhydrous THF (40mL) solution in adds reactant mixture and allows at room temperature to carry out reacting overnight, thus causing white depositions to dissolve And form shallow grass color suspension (pale straw suspension).Then add at 0 DEG C pure acetaldehyde (121.32mL, 2.134mol, 30.0 equivalents) and stirring mixture 5 hours.Remove volatile matter under reduced pressure.Add ether (125mL), then frequency Any alcohol (10.08g, 85.36mmol, 1.2 equivalent).Allow stirring mixture overnight at room temperature.Mixture is absorbed in DCM (125mL), in, washed with water (2x75mL), then dried over magnesium sulfate.To remove volatile matter and to lead to by concentrating under reduced pressure Cross flash chromatography (0/100 to 60/40 ethyl acetate/hexane v/v) and carry out purification residue.Merging product frac is simultaneously dense under reduced pressure Contracting, to produce water white oil, is absorbed in a small amount of DCM, is cooled to -78 DEG C, then adds hexane heavy until forming white Starch.Allow stirred suspension 5 minutes and filter, to provide product, as white solid (14.09g, 49%).LC/MS (point Clock (ES+)).m/z:[M]+.1H NMR(400MHz,CDCl3)), δ 7.76 (d, 2H, J=7.6Hz), 7.59 (d, 2H, J= 7.4Hz), 7.40 (t, 2H, J=7.4Hz), 7.32 (t, 2H, J=7.4Hz), 6.59 (dt, 1H, J=18.0,4.7Hz), 5.60 (d, 2H, J=18.0Hz), 4.90-4.83 (m, 1H), 4.40 (d, 2H, J=7.1Hz), 4.22 (t, 1H, J=7.1Hz), 3.92 (t, 1H, J=4.7Hz), 1.27 (s, 12H).
(iii) (S) -2- ((S) -2- (((9H- fluorenes -9- base) methoxyl group) carbonylamino) -3- methylbutyrylamino) propanoic acid (HO-Ala-Val-Fmoc)(12)
By H-Val-Ala-OH11 (1.0g, 5.313mmol, 1.0 equivalent) and Na2CO3(1.42g, 13.282mmol, 2.5 Equivalent) it is dissolved in distillation H2O (40mL), and adding dioxane (40mL) in the past, mixture is cooled to 0 DEG C.Send out The partly precipitated of raw amino acid salts.With vigorous stirring, through 10 minutes, (1.44g, 5.579mmol, 1.05 work as Deca Fmoc-Cl Amount) it is dissolved in solution in dioxane (40mL).Before removing ice bath, at 0 DEG C, the mixture 2 that stirring produces Hour, then continuously stirred 16 hours.Evaporation solvent remaining solid is dissolved in water (450mL) under reduced pressure.Use 1N HCl (25mL) by pH regulator to 2, EtOAc (3x250mL) is subsequently used to extract water layer.To wash the organic of merging with saline (100mL) Thing, through MgSO4It is dried, filter and remove volatile matter under reduced pressure, to provide pure HO-Ala-Val-Fmoc12, solid for white Body (2.06g, 94%).LC/MS (2.758 minutes (ES+)),m/z:411.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ 12.47 (br s, 1H), 8.20 (d, 1H, J=6.7Hz), 7.89 (d, 2H, J=7.5Hz), 7.75 (t, 2H, J=6.8Hz), 7.43 7.38 (m, 3H), 7.34 7.30 (m, 2H), 4.31 4.16 (m, 4H), 3.88 (dd, 1H, J=8.8,7.2Hz), 1.98 (m, 1H), 1.26 (d, 3H, J=7.3Hz), 0.89 (d, 3H, J=6.8Hz), 0.86 (d, 3H, J=6.8Hz).
Embodiment 2
(a) (S) -8- (3- ((S) -2- ((E) -3- (((9H- fluorenes -9- base) methoxyl group) carbonylamino) propyl- 1- thiazolinyl) -7- Methoxyl group -5,11- dioxy -10- ((2- (trimethyl silyl) ethyoxyl) methyl) -5,10,11,11a- tetrahydrochysene -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 8- base epoxide) propoxyl group) -7- methoxyl group -5,11- dioxy -10- ((2- (three Methyl silicane base) ethyoxyl) methyl) -5,10,11,11a- tetrahydrochysene -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 2- base trifluoromethayl sulfonic acid ester (13)
Suspension in toluene (6mL) for the borate 10 (2.19g, 5.61mmol, 0.95 equivalent) was dropwise added through 1 hour Enter diene alcohol triflate 7 (6.6g, 5.91mmol, 1.0 equivalent), four (triphenyl phasphine) palladium (0) (0.273g, 0.236mmol, 0.04 equivalent), sodium carbonate (2.00g, 18.91mmol, 3.2 equivalent) methanol (28mL), toluene (56mL) and Agitating solution in water (34mL).Allow stirring reaction mixture overnight at room temperature, be then concentrated to dryness, residue is inhaled It is received in EtOAc (200mL) and washed with water (2x150mL), saline (150mL), through MgSO4It is dried, filtered and concentrated and (subtracting Pressure).By flash chromatography (silica gel, 80:20 hexanes/EtOAc v/v to 10:90 hexanes/EtOAc, then pure EtOAc) next pure Change crude product, with provide recovery 7, product and dibasic impurity.The 13 of 2.49g (37%) are yellow solid.LC/MS (3.930 minutes (ES+)),m/z:1247.39[M+H]+.1H NMR(400MHz,CDCl3) δ 7.78 (d, 2H, J=7.6Hz), 7.60 (d, 2H, J=7.4Hz), 7.41 (t, 2H, J=7.6Hz), 7.36 7.31 (m, 1H), 7.14 (m, 1H), 6.96 (m, 1H), 6.36 (d, 1H, J=14.4Hz), 5.69 5.59 (m, 1H), 5.51 (dd, 2H, J=10.1,3.0Hz), 4.87 4.81 (m, 1H), 4.75 (dd, 2H, J=10.1,7.9Hz), 4.61 (dd, 1H, J=10.9,3.6Hz), 4.54 (dd, 2H, J= 10.6,3.3Hz), 4.43 (d, 2H, J=6.6Hz), 4.31-4.20 (m, 6H), 3.95 3.87 (m, 9H), 3.81 3.63 (m, 6H), 3.15 (ddd, 1H, J=16.2,10.9,2.3Hz), 2.93-2.83 (m, 1H), 2.43 (hep, 1H, J=5.8Hz), 1.00–0.92(m,4H),0.01(s,18H).The 7 of 2.06g (33%).LC/MS (3.916 minutes (ES+)).The two of 0.770g take The impurity in generation, as yellow solid.LC/MS (3.977 minutes (ES+)).m/z:1376.52[M+H]+.
(b) compound 14a-e
(i) (9H- fluorenes -9- base) methyl (E) -3- ((S) -7- methoxyl group -8- (3- ((S) -7- methoxyl group -2- methyl -5, 11- dioxy -10- ((2- (trimethyl silyl) ethyoxyl) methyl) -5,10,11,11a- tetrahydrochysene -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 8- epoxide) propoxyl group) -5,11- dioxy -10- ((2- (trimethyl silyl) ethyoxyl) Methyl) -5,10,11,11a- tetrahydrochysene -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 2- base) allyl amino first Acid esters (14a)
Under nitrogen atmosphere, triphenylarsine (0.010g, 0.0321mmol, 0.8 equivalent) is added triflate 13 (0.050g, 0.0401mmol, 1.0 equivalent), methyl-boric acid (0.012g, 0.20mmol, 5.0 equivalent), silver oxide (0.074g, 0.321mmol, 8.0 equivalents) and tripotassium phosphate (0.102g, 0.481mmol, 12.0 equivalent) in anhydrous dioxane (2mL) mixture in.It is purged with nitrogen and react and add double (benzonitrile) Palladous chloride. (II) (0.003g, 0.00802mmol, 0.2 Equivalent).Before being heated to 70 DEG C, it is purged with nitrogen reaction 1 hour again.Triflate 13 to 0.200g, weight Multiple above-mentioned reaction condition, and pass throughPad filters the reactant mixture of merging with ethyl acetate washings.Dense under reduced pressure Contracting crude material simultaneously provides product by flash chromatography, is faint yellow solid (0.010g, 56%).LC/MS(3.823 Minute (ES+)),m/z:1112.92[M+H]+.
(ii) (9H- fluorenes -9- base) methyl (E) -3- ((S) -7- methoxyl group -8- (3- ((S) -7- methoxyl group -5,11- dioxy - 2- ((E) -propyl- 1- thiazolinyl) -10- ((2- (trimethyl silyl) ethyoxyl) methyl) -5,10,11,11a- tetrahydrochysene -1H- benzene And [e] pyrrolo- [1,2-a] [1,4] diaza- 8- epoxide) propoxyl group) -5,11- dioxy -10- ((2- (trimethyl first silicon Alkyl) ethyoxyl) methyl) -5,10,11,11a- tetrahydrochysene -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 2- base) Allyl carbamate (14c)
Under nitrogen atmosphere, by anti-form-1-propylene-1- ylboronic acid (0.103g, 1.20mmol, 3.0 equivalent), triethylamine (0.220ml, 1.60mmol, 4.0 equivalent) and single triflate 13 (0.500g, 0.401mmol, 1.0 equivalent) are dissolved in The mixture of ethanol (10mL), toluene (20mL) and water (3mL).Degassing reactant mixture 5 minutes add four (three under a nitrogen Phosphniline) palladium (0) (0.018g, 0.016mmol, 0.04 equivalent).Stirring reaction mixture 50 minutes at 60 DEG C, then in decompression Under be concentrated to dryness and pass through flash chromatography (silica gel, 50:50 acetass/hexane v/v, then 66:33 ethyl acetate/hexane v/ V) carry out purification of crude solid, to provide product, be faint yellow solid (0.35g, 77%).LC/MS (3.910 minutes (ES+)),m/ z:1137.86[M+H]+.
(iii) (9H- fluorenes -9- base) methyl (E) -3- ((S) -8- (3- ((S) -2- (benzo [d] [1,3] dioxy l-5- yl) - 7- methoxyl group -5,11- dioxy -10- ((2- (trimethyl silyl) ethyoxyl) methyl) -5,10,11,11a- tetrahydrochysene -1H- benzene And [e] pyrrolo- [1,2-a] [1,4] diaza- 8- epoxide) propoxyl group) -7- methoxyl group -5,11- dioxy -10- ((2- (three Methyl silicane base) ethyoxyl) methyl) -5,10,11,11a- tetrahydrochysene -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 2- base) allyl carbamate (14d)
Under a nitrogen, by 3,4- (methylene-dioxy) phenylboric acid (0.027g, 0.160mmol, 2.0 equivalent), triethylamine (0.065g, 0.064mmol, 8.0 equivalent) and single triflate 13 (0.100g, 0.080mmol, 1.0 equivalent) are dissolved in The mixture of ethanol (1mL), toluene (2mL) and water (0.4mL).Emptying reaction vessel is simultaneously adding four (triphenyl phasphine) palladium (0) (0.006g, 0.005mmol, 0.06 equivalent) in the past, is purged with nitrogen three times.Then empty flask, and be purged with nitrogen three times, Then heat 8 minutes under microwave radiation and at 80 DEG C.Repeat above-mentioned reaction twice in 0.100g scale, and 0.130g is advised Mould repeats above-mentioned reaction once.Merge crude reaction mixture, diluted and used H with DCM (10mL)2O (10mL) washs.Through MgSO4 Organic layer is dried, filters and concentrate (under reduced pressure), and pass through flash chromatography (silica gel, 30/70 to 20/80v/v hexane/acetic acid Ethyl ester) carry out purification residue, to provide product, it is faint yellow solid (0.199g, 62%).LC/MS (3.887 minutes (ES+)), m/z:1217.57[M+H]+.1H NMR(400MHz,CDCl3) δ 7.77 (d, 2H, J=7.4Hz), 7.60 (d, 2H, J= 7.5Hz), 7.43 7.29 (m, 7H), 6.97 6.94 (m, 2H), 6.88 (dd, 2H, J=7.8,1.7Hz), 6.78 (d, 2H, J= 8.1Hz), 6.35 (d, 1H, J=15.7Hz), 5.97 (s, 2H), 5.69 5.59 (m, 1H), 5.50 (dd, 2H, J=10.1, 2.7Hz), 4.84 (m, 1H), 4.75 (dd, 2H, J=10.1,5.8Hz), 4.61 4.52 (m, 3H), 4.44 (d, 1H, J= 6.9Hz), 4.32-4.20 (m, 6H), 3.94 3.87 (m, 9H), 3.81 3.64 (m, 6H), 3.15 (ddd, 1H, J=16.2, 10.6,1.9Hz),2.88(m,1H),2.43(m,1H),0.99–0.95(m,4H),0.01(s,18H).
(iv) (9H- fluorenes -9- base) methyl (E) -3- ((S) -7- methoxyl group -8- (3- ((S) -7- methoxyl group -2- (4- (4- first Base piperazine -1- base) phenyl) -5,11- dioxy -10- ((2- (trimethyl silyl) ethyoxyl) methyl) -5,10,11,11a- Tetrahydrochysene -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 8- epoxide) propoxyl group) -5,11- dioxy -10- ((2- (trimethyl silyl) ethyoxyl) methyl) -5,10,11,11a- tetrahydrochysene -1H- benzo [e] pyrrolo- [1,2-a] [1,4] two Azepine- 2- base) allyl carbamate (14e)
Under nitrogen atmosphere, by single triflate 13 (0.100g, 0.0802mmol, 1.0 equivalent), (4- methyl piperazine- 1- yl) phenylboric acid, pinacol ester (0.023g, 0.0762,0.95 equivalent) and triethylamine (0.051mL, 0.369mmol, 4.6 Equivalent) it is dissolved in toluene/ethanol/H2O[6:3:1] mixture of (4mL).It is purged with nitrogen reaction 5 minutes and add palladium-four three Phosphniline (0.9mg, 0.000802mmol, 0.01 equivalent).Then reaction is made to stand microwave radiation 5 minutes at 80 DEG C.Right 0.100g scale, repeats above-mentioned reaction 3 times.Concentrate the reactant mixture of merging under reduced pressure, and in H2O (180mL) and acetic acid Solid residue is distributed between ethyl ester (180mL).Before wash the Organic substance merging with saline (180mL), use ethyl acetate (2x180mL) extract water layer, through MgSO4, it is dried, filtered and concentrated (under reduced pressure).By flash chromatography (silica gel, 40:1v/v DCM/MeOH to 20:1v/v DCM/MeOH) carry out the crude mixture that purification produces, to provide desired product, as yellow Solid (0.220g, 54%), LC/MS (2.833 minutes (ES+)),m/z:1272.53[M+H]+.1H NMR(400MHz,CDCl3) δ 7.77 (d, 2H, J=7.5Hz), 7.60 (d, 2H, J=7.3Hz), 7.43 7.39 (m, 3H), 7.35 7.30 (m, 6H), 6.95 (m, 1H), 6.90 6.87 (m, 1H), 6.34 (d, 1H, J=15.7Hz), 5.67 5.57 (m, 1H), 5.50 (dd, 2H, J= ), 10.1,3.3Hz 4.86 (m, 1H), 4.75 (dd, 2H, J=10.1,5.6Hz), 4.54 (m, 2H), 4.44 (d, 2H, J= 6.8Hz),4.31–4.21(m,6H),3.96–3.87(m,9H),3.81–3.73(m,3H),3.71–3.62(m,3H),3.31– 3.20(m,5H),3.10(m,1H),2.87(m,1H),2.58(m,4H),2.43(m,2H),2.36(s,3H),0.97(m,4H), 0.01(s,18H).
(c) compound 15a-e
(i) (9H- fluorenes -9- base) methyl (E) -3- ((S) -8- (3- ((S) -2- (benzo [d] [1,3] dioxy l-5- yl) -7- Methoxyl group -5- oxygen -5,11a- dihydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 8- epoxide) propoxyl group)- 7- methoxyl group -5- oxygen -5,11a- dihydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 2- base) allyl amino Formic acid esters (15d)
Under nitrogen atmosphere, double for SEM lactams 14d (0.223g, 0.183mmol, 1.0 equivalent) are dissolved in THF (10mL) And it is cooled to -78 DEG C.Through 5 minutes, the super hydride solution of Deca (0.373mL, 0.373mmol, 2.04 equivalent).20 minutes with Afterwards, wash aliquot with water, for LCMS and TLC analysis, and after 30 minutes, add water (30mL) and remove cryostat. Extract organic layer with EtOAc (2x30mL) and wash, with saline (30mL), the organic extract merging, through MgSO4It is dried, filter And concentrate (under reduced pressure).Crude product is dissolved in MeOH (12mL), DCM (6mL) and water (2mL) and enough silica gel with shape Become dense stirred suspension, it is allowed to stand for 5 days.Filter suspension and use DCM/MeOH9:1 (~200mL) washs until product Complete eluting.Wash organic layer with saline (2x70mL), through MgSO4It is dried, filter and concentrate (under reduced pressure) and by fast Speed chromatography (silica gel, 100/0 to 90/10v/vCHCl3/ MeOH) carry out purification residue, to provide product, as yellow solid (0.133g, 79%).LC/MS (2.916 minutes (ES+)),m/z:926.33[M+H]+.
(ii) (9H- fluorenes -9- base) methyl (E) -3- ((S) -7- methoxyl group -8- (3- ((S) -7- methoxyl group -2- (4- (4- first Base piperazine -1- base) phenyl) -5- oxygen -5,11a- dihydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 8- oxygen Base) propoxyl group) -5- oxygen -5,11a- dihydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 2- base) pi-allyl ammonia Carbamate (15e)
Under nitrogen atmosphere, double for SEM lactams 14e (0.250g, 0.196mmol, 1.0 equivalent) are dissolved in THF (13mL) And it is cooled to -78 DEG C.Through 5 minutes, the super hydride solution of Deca (0.40mL, 0.401mmol, 2.04 equivalent).20 minutes with Afterwards, wash aliquot with water, for LCMS and TLC analysis.After 30 minutes, add water (30mL) and remove cryostat.With EtOAc (2x40mL) extracts organic layer and washs the organic extract merging with saline (40mL), uses MgSO4Be dried, filter and Remove (under reduced pressure).Crude product is dissolved in MeOH (13mL), DCM (7mL) and water (1.7mL) and enough silica gel is with shape Become dense stirred suspension.After 5 days, filter suspension by sinter funnel and use DCM/MeOH9:1 (~200mL) Washing is until the complete eluting of product.To wash organic layer with saline (2x70mL), to use MgSO4It is dried, filter and remove solution (under reduced pressure).By flash chromatography (silica gel, CHCl3100 to 96:4v/v CHCl3/ MeOH) carry out purification to produce product, For faint yellow solid (0.090g, 47%).LC/MS (2.112 minutes (ES+)),m/z:981.0[M+H]+.
(d) compound 16a-e
(i) (S) -2- ((E) -3- amino propyl- 1- thiazolinyl) -8- (3- ((S) -2- (benzo [d] [1,3] dioxy -5- base) -7- Methoxyl group -5- oxygen -5,11a- dihydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 8- epoxide) propoxyl group)- 7- methoxyl group -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 5 (11aH) -one (16d)
Piperidines (6, excessive) is added Fmoc allylamine 15d (0.030g, 0.0306mmol, 1.0 equivalent) in dry DMF (0.30mL) stirring mixture at ambient temperature stirring mixture.After 20 minutes, the LCMS of reactant mixture Display reaction completes, and then washs with DCM (30mL) diluted reaction mixture and with water (3x30mL).Through MgSO4To be dried Machine layer, filters and concentrates (under reduced pressure).Crude material is dissolved in chloroform and by filtering collecting the precipitate obtaining, with There is provided product, as orange solids (0.003g, 13%).LC/MS (1.802 minutes (ES+)),m/z:704.1[M+H]+.
(ii) (S) -2- ((E) -3- amino propyl- 1- thiazolinyl) -7- methoxyl group -8- (3- ((S) -7- methoxyl group -2- (4- (4- Methylpiperazine-1-yl) phenyl) -5- oxygen -5,11a- dihydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza-8- Epoxide) propoxyl group) -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 5 (11aH) -one (16e)
Piperidines (4, excessive) is added Fmoc allyl amine 15e (0.02g, 0.0204mmol, 1.0 equivalent) anhydrous Stirring mixture in DMF (0.25mL), then stirring mixture at ambient temperature.After 30 minutes, with DCM (30mL) Carry out diluted reaction mixture and washed with water (3x30mL).Through MgSO4Organic layer is dried, filters and concentrate (under reduced pressure). Crude material is dissolved in chloroform and by filtering collecting the precipitate obtaining, to provide product, as orange solids (0.001g, 7%).LC/MS (1.495 minutes (ES+)),m/z:379.51/2[M+2H]+.
Synthesis key intermediate
1- iodo- 2- oxygen -6,9,12,15- four oxa- -3- azepine octadecane -18- acid (I5)
Solution in anhydrous DCM (1mL) for the iodoacetic acid acid anhydride (0.250g, 0.706mmol, 1.1 equivalent) is added in DCM (1mL) amino-PEG in(4)- sour I4 (0.170g, 0.642mmol, 1.0 equivalent).In the dark and mixing is stirred at room temperature Thing is overnight.With 0.1M HCl, water washing reactant mixture, through MgSO4It is dried, filter and concentrate (under reduced pressure), by quick It is residual that chromatography (silica gel, 3%MeOH and 0.1% formic acid, in chloroform, to 10%MeOH and 0.1% formic acid, in chloroform) carrys out purification Excess, to provide product, as orange oil (0.118g, 42%).LC/MS (1.623 minutes (ES+)),m/z:433..98[M+ H]+.1H NMR(400MHz,CDCl3) δ 8.069 (s, 1H), 7.22 (br s, 1H), 3.79 (t, 2H, J=5.8Hz), 3.74 (s, 2H), 3.72 3.58 (m, 14H), 3.50 3.46 (m, 2H), 2.62 (t, 2H, J=5.8Hz).
Embodiment 3
(a) compound 17a-e
(i) (S) -2- ((E) -3- amino propyl- 1- thiazolinyl) -7- methoxyl group -8- (3- ((S) -7- methoxyl group -2- methyl -5, 11- dioxy -10- ((2- (trimethyl silyl) ethyoxyl) methyl) -5,10,11,11a- tetrahydrochysene -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 8- epoxide) propoxyl group) -10- ((2- (trimethyl silyl) ethyoxyl) methyl) -1H- benzene And [e] pyrrolo- [1,2-a] [1,4] diaza- 5,11 (10H, 11aH)-diketone (17a)
Piperidines (0.133mL, 1.35mmol, 12 equivalent) is added Fmoc amine 14a, and (0.125g, 0.112mmol, 1.0 work as Amount) agitating solution in DMF (1.8ml).After being stirred at room temperature 30 minutes, lcms analysis show disappearing of parent material Consumption, and with DCM (200mL) diluted reaction mixture, then washed with water (3x200mL).Through MgSO4Organic layer, mistake are dried Filter and be concentrated to dryness, to provide crude product, it does not experience further purification (0.100g it is assumed that 100% yield).Make Use this material, without further characterization.
(ii) (S) -2- ((E) -3- amino propyl- 1- thiazolinyl) -7- methoxyl group -8- (3- ((S) -7- methoxyl group -5,11- two Oxygen -2- ((E) -propyl- 1- thiazolinyl) -10- ((2- (trimethyl silyl) ethyoxyl) methyl) -5,10,11,11a- tetrahydrochysene -1H- Benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 8- epoxide) propoxyl group) -10- ((2- (trimethyl silyl) ethoxy Base) methyl) -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 5,11 (10H, 11aH)-diketone (17c)
Piperidines (0.40mL, 4.0mmol, 12 equivalent) is added Fmoc amine 14c (0.380g, 0.334mmol, 1.0 equivalent) Agitating solution in DMF (5.0mL).After being stirred at room temperature 20 minutes, lcms analysis show the consumption of parent material, so Wash with DCM (300mL) diluted reaction mixture and with water (3x300mL) afterwards.Through MgSO4Organic layer is dried, filters and dense It is reduced to and (under reduced pressure) is dried, to provide crude product, it does not experience further purification, and (0.306g is it is assumed that 100% produces Rate).
LC/MS (2.533 minutes (ES+)),m/z:916.3[M+H]+.
(iii) (S) -2- ((E) -3- amino propyl- 1- thiazolinyl) -7- methoxyl group -8- (3- ((S) -7- methoxyl group -2- (4- (4- Methylpiperazine-1-yl) phenyl) -5,11- dioxy -10- ((2- (trimethyl silyl) ethyoxyl) methyl) -5,10,11, 11a- tetrahydrochysene -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 8- epoxide) propoxyl group) -10- ((2- (trimethyl Silicyl) ethyoxyl) methyl) -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 5,11 (10H, 11aH)-two Ketone (17e)
Piperidines (0.40mL, 4.0mmol, 14.2 equivalent) is added Fmoc amine 14e, and (0.358g, 0.282mmol, 1.0 work as Amount) agitating solution in DMF (5.0mL).Above-mentioned clear solution is stirred at room temperature 30 minutes.Anti- with DCM (300mL) dilution Answer mixture and washed with water (3x300mL).Through MgSO4Organic layer is dried, filters and concentrate (under reduced pressure), thick to provide Product, it does not experience further purification (0.296g it is assumed that 100% yield).LC/MS (2.049 minutes (ES+)),m/ z:1051.2[M+H]+.
(b) compound 18a-e
(i) (9H- fluorenes -9- base) methyl (R) -1- ((S) -1- ((E) -3- ((S) -7- methoxyl group -8- (3- ((S) -7- methoxy Base -2- methyl -5,11- dioxy -10- ((2- (trimethyl silyl) ethyoxyl) methyl) -5,10,11,11a- tetrahydrochysene -1H- Benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 8- epoxide) propoxyl group) -5,11- dioxy -10- ((2- (trimethyl first silicon Alkyl) ethyoxyl) methyl) -5,10,11,11a- tetrahydrochysene -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 2- base) Allyl amino) -1- oxygen propyl- 2- base amino) -3- methyl isophthalic acid-oxygen butyl- 2- aminocarbamic acid ester (18a)
By 1- ethyl -3- (3 '-dimethylaminopropyl) carbodiimide hydrochloride, (0.018g, 0.095mmol, 1.0 work as Amount) add allylamine 17a (it is assumed that 100% yield, 0.100g, 0.095mmol, 1.0 equivalents) and HO-Ala-Val-Fmoc12 (0.036g, 0.095mmol, 1.0 equivalent) solution in anhydrous methylene chloride (6mL).Reactant mixture is stirred at room temperature 120 minutes, at that time, with dichloromethane (10mL) diluted reaction mixture, and washed successively with water (10mL) and saline (10mL). Through MgSO4Organic layer is dried, filters and remove excessive dichloromethane (under reduced pressure).By flash chromatography (silica gel;100: 1v/v DCM/MeOH to 40:1v/v DCM/MeOH) carry out the residue that purification produces, to provide product, as yellow solid (0.050g, 35%).LC/MS (3.677 minutes (ES+)),m/z:1281.42[M+H]+.1H NMR(400MHz,CDCl3)δ 7.76 (d, 2H, J=7.7Hz), 7.58 (m, 2H), 7.40 (t, 2H, J=7.6Hz), 7.34 (d, 2H, J=5.7Hz), 7.31 (m,3H),7.25(m,2H),6.93(s,1H),6.68(m,1H),6.34(m,3H),5.58(m,1H),5.49(m,2H),4.71 (m, 2H), 4.45 (m, 5H), 4.27 (m, 4H), 4.22 (t, 1H, J=7.0Hz), 3.97 (m, 2H), 3.89 (m, 7H), 3.75 (m, 2H), 3.65 (m, 3H), 3.44 (m, 1H), 2.77 (m, 2H), 2.43 (m, 2H), 2.14 (m, 1H), 1.83 (d, 3H, J= 1.0Hz), 1.40 (d, 3H, J=6.9Hz), 0.99 0.91 (m, 10H), 0.01 (s, 9H), 0.00 (s, 9H).
(ii) (9H- fluorenes -9- base) methyl (S) -1- ((S) -1- ((E) -3- ((S) -7- methoxyl group -8- (3- ((S) -7- first Epoxide -5,11- dioxy -2- ((E) -propyl- 1- thiazolinyl) -10- ((2- (trimethyl silyl) ethyoxyl) methyl) -5,10,11, 11a- tetrahydrochysene -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 8- epoxide) propoxyl group) -5,11- dioxy -10- ((2- (trimethyl silyl) ethyoxyl) methyl) -5,10,11,11a- tetrahydrochysene -1H- benzo [e] pyrrolo- [1,2-a] [1, 4] diaza- 2- base) allyl amino) -1- oxygen propyl- 2- base amino) -3- methyl isophthalic acid-oxygen butyl- 2- aminocarbamic acid ester (18c)
By 1- ethyl -3- (3 '-dimethylaminopropyl) carbodiimide hydrochloride, (0.0641g, 0.334mmol, 1.0 work as Amount) add allylamine 17c (it is assumed that 100% yield, 0.306g, 0.334mmol, 1.0 equivalents) and HO-Ala-Val-Fmoc12 (0.1367g, 0.334mmol, 1.0 equivalent) solution in anhydrous methylene chloride (18mL).At room temperature, stirring reaction mixing Thing 95 minutes, at that time, washs with dichloromethane (30mL) diluted reaction mixture and successively with water (30mL) and saline (30mL). Through MgSO4Organic layer is dried, filters and remove excessive dichloromethane (under reduced pressure).By flash chromatography (silica gel;100: 1v/v DCM/MeOH to 40:1v/vDCM/MeOH) carry out the residue of purification generation, to provide product, be yellow solid (0.220g, 50%).LC/MS (3.804 minutes (ES+)),m/z:1307.37[M+H]+.1H NMR(400MHz,CDCl3)δ 7.76 (d, 2H, J=7.6Hz), 7.57 (m, 2H), 7.39 (t, 2H, J=7.6Hz), 7.34 (d, 2H, J=3.2Hz), 7.31 (m, 3H), 7.26 (m, 1H), 6.93 (s, 1H), 6.85 (m, 1H), 6.36 (m, 2H), 6.24 (d, 1H, J=14.7Hz), 5.68 (m,1H),5.58(m,1H),5.49(m,2H),4.72(m,2H),4.83(m,4H),4.39(m,1H),4.27(m,4H),4.22 (t, 1H, J=6.9Hz), 3.98 (m, 3H), 3.89 (m, 8H), 3.75 (m, 2H), 3.65 (m, 4H), 2.85 (m, 2H), 2.43 (m, 2H), 2.14 (m, 1H), 1.82 (dd, 3H, J=5.8,0.8Hz), 1.40 (d, 3H, J=6.9Hz), 0.99 0.92 (m, 10H),0.01(s,9H),0.00(s,9H).
(iii) (9H- fluorenes -9- base) methyl (S) -1- ((S) -1- ((E) -3- ((S) -7- methoxyl group -8- (3- ((S) -7- first Epoxide -2- (4- (4- methylpiperazine-1-yl) phenyl) -5,11- dioxy -10- ((2- (trimethyl silyl) ethyoxyl) first Base) -5,10,11,11a- tetrahydrochysene -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 8- epoxide) propoxyl group) -5, 11- dioxy -10- ((2- (trimethyl silyl) ethyoxyl) methyl) -5,10,11,11a- tetrahydrochysene -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 2- base) allyl amino) -1- oxygen propyl- 2- base amino) -3- methyl isophthalic acid-oxygen butyl- 2- base ammonia Carbamate (18e)
By 1- ethyl -3- (3 '-dimethylaminopropyl) carbodiimide hydrochloride, (0.0541g, 0.282mmol, 1.0 work as Amount) add allylamine 17e (it is assumed that 100% yield, 0.296g, 0.282mmol, 1.0 equivalents) and HO-Ala-Val-Fmoc12 (0.116g, 0.282mmol, 1.0 equivalent) solution in anhydrous methylene chloride (18mL).At room temperature, stirring reaction mixing Thing 80 minutes, at that time, washs with dichloromethane (30mL) diluted reaction mixture and successively with water (30mL) and saline (30mL). Through MgSO4Organic layer is dried, filters and remove excessive dichloromethane (under reduced pressure).By flash chromatography (silica gel;40:1v/ V DCM/MeOH to 20:1v/v DCM/MeOH) come purification generation residue, to provide product, be yellow solid (0.245g, 60%).LC/MS (2.706 minutes (ES+)),m/z:721.51/2[M+2H]+.
(c) compound 19a-e
(i) (9H- fluorenes -9- base) methyl (S) -1- ((S) -1- ((E) -3- ((S) -7- methoxyl group -8- (3- ((S) -7- methoxy Base -5- oxygen -2- ((E) -propyl- 1- thiazolinyl) -5,11a- dihydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza-8- Epoxide) propoxyl group) -5- oxygen -5,11a- dihydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 2- base) allyl Base amino) -1- oxygen propyl- 2- base amino) -3- methyl isophthalic acid-oxygen butyl- 2- aminocarbamic acid ester (19c)
Under nitrogen atmosphere, SEM Fmoc amine 18c (0.212g, 0.162mmol, 1.0 equivalent) is dissolved in THF (9.2mL) And it is cooled to -78 DEG C.Through 4 minutes, the super hydride solution of Deca (0.330mL, 0.330mmol, 2.04 equivalent).45 minutes with Afterwards, dilute aliquot with water and MeOH, for LCMS.After other 10 minutes of stirring, mixed with water (27mL) diluting reaction Compound simultaneously removes cryostat.Extract organic layer with EtOAc (2x27mL) and wash the organic extract merging, warp with saline (27mL) MgSO4Carry out drying, filter and concentrate (under reduced pressure).Crude product is dissolved in MeOH (11.05mL), DCM (5.53mL) and water (1.85mL), and add enough silica gel, to form dense suspension, it is stirred with 5 days.Filter suspension and use DCM/ MeOH9:1 (~200mL) washs, until the complete eluting of product.Wash organic layer with saline (2x70mL), through MgSO4It is dried, Filter and concentrate (under reduced pressure).By flash chromatography (silica gel;40:1v/v DCM/MeOH to 20:1v/v DCM/MeOH) come The residue that purification produces, to provide product, as yellow solid (0.060g, 36%).LC/MS (2.802 minutes (ES+)), m/z:1016.15[M+H]+.
(ii) (9H- fluorenes -9- base) methyl (R) -1- ((S) -1- ((E) -3- ((S) -7- methoxyl group -8- (3- ((S) -7- first Epoxide -2- (4- (4- methylpiperazine-1-yl) phenyl) -5- oxygen -5,11a- dihydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] Diaza- 8- epoxide) propoxyl group) -5- oxygen -5,11a- dihydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza - 2- base) allyl amino) -1- oxygen propyl- 2- base amino) -3- methyl isophthalic acid-oxygen butyl- 2- aminocarbamic acid ester (19e)
Under nitrogen atmosphere, SEM Fmoc amine 18e (0.245g, 0.170mmol, 1.0 equivalent) is dissolved in THF (10.6mL) And it is cooled to -78 DEG C.Through 4 minutes, the super hydride solution of Deca (0.347mL, 0.347mmol, 2.04 equivalent).45 minutes with Afterwards, dilute aliquot with water and MeOH, for LCMS.After other 10 minutes of stirring, with the mixing of water (35mL) diluting reaction Thing simultaneously removes cryostat.Extract organic layer with EtOAc (2x35mL), and wash the organic extract merging with saline (35mL), use MgSO4It is dried, filter and concentrate (under reduced pressure).Crude material is dissolved in MeOH (12.8mL), DCM (6.4mL) and water (2.15mL), and add enough silica gel to form dense suspension, it is stirred with 5 days.Filter suspension and use DCM/ MeOH9:1 (~200mL) washs, until the complete eluting of product.Wash organic layer with saline (2x100mL), through MgSO4Dry Dry, filter and concentrate (under reduced pressure).By flash chromatography (silica gel;40:1v/v DCM/MeOH to 20:1v/v DCM/MeOH) Carry out the residue of purification generation, to provide product (0.100g, 51%).LC/MS (2.117 minutes (ES+)),m/z:575.71/2 [M+2H]+.
(a) compound 20a-e
(i) (S) -2- amino-N- ((S) -1- ((E) -3- ((S) -7- methoxyl group -8- (3- ((S) -7- methoxyl group -5- oxygen - 2- ((E) -propyl- 1- thiazolinyl) -5,11a- dihydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 8- epoxide) the third oxygen Base) -5- oxygen -5,11a- dihydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 2- base) allyl amino) -1- Oxygen propyl- 2- yl) -3- methylbutyryl amine (20c)
Piperidines (0.04mL, 4.1mmol, 13.7 equivalent) is added Fmoc amine 19c (0.030g, 0.0295mmol, 1 equivalent) Stirring mixture in dry DMF (0.5mL), then stirring mixture at ambient temperature.After 20 minutes, LCMS shows Show that reaction completes, then wash with DCM (75mL) diluted reaction mixture and with water (3x75mL).Through MgSO4Organic to be dried Layer, filters and is concentrated to dryness (under reduced pressure).Carry out coevaporation to obtain product together with normal hexane, as brown oil, and And this material is not further subjected to purification (0.023g it is assumed that 100%).LC/MS (1.868 minutes (ES+)),m/z:794.2 [M+H]+.
(ii) (S) -2- amino-N- ((S) -1- ((E) -3- ((S) -7- methoxyl group -8- (3- ((S) -7- methoxyl group -2- (4- (4- methylpiperazine-1-yl) phenyl) -5- oxygen -5,11a- dihydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza8- Epoxide) propoxyl group) -5- oxygen -5,11a- dihydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza2- yl) pi-allyl Amino) -1- oxygen propyl- 2- yl) -3- methylbutyryl amine (20e)
Piperidines (0.058mL, 0.590mmol, 12.0 equivalent) is added Fmoc amine 19e (0.050g, 0.0492mmol, 1.0 Equivalent) stirring mixture in dry DMF (0.8mL), then stirring mixture at ambient temperature.After 20 minutes, LCMS display reaction completes, and then washs with DCM (30mL) diluted reaction mixture and with water (3x30mL).Through MgSO4To do Dry organic layer, filters and is concentrated to dryness (under reduced pressure).Carry out coevaporation to obtain product together with normal hexane, be brown Oil, and this material is not further subjected to purification (0.040g it is assumed that 100%).LC/MS (1.533 minutes (ES+)),m/z: 928.2[M+H]+.
(a) compound 21a-e
(i) 1- (2- iodacetyl amino)-N- ((S) -1- ((S) -1- ((E) -3- ((S) -7- methoxyl group -8- (3- ((S) -7- Methoxyl group -5- oxygen -2- ((E) -propyl- 1- thiazolinyl) -5,11a- dihydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 8- epoxide) propoxyl group) -5- oxygen -5,11a- dihydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza- 2- base) Allyl amino) -1- oxygen propyl- 2- base amino) -3- methyl isophthalic acid-oxygen butyl- 2- yl) -3,6,9,12- four oxa- pentadecane -15- acyl Amine (21c)
By 2- ethyoxyl -1- ethoxy carbonyl -1,2- dihydroquinoline (0.007g, 0.0290mmol, 1.0 equivalent) adds amine 20c (it is assumed that 100%, 0.023g, 0.0290mmol, 1.0 equivalent) and 1- iodo- 2- oxygen -6,9,12,15- tetra- oxa- -3- azepines ten Eight alkane -18- acid (I5) (0.0126g, 0.0290mmol, 1.0 equivalent) solution in anhydrous methylene chloride (2mL).Stirring is anti- Answer mixture 18 hours, then diluted with DCM (6mL) and washed with water (2x10mL).Through MgSO4Organic layer is dried, filters With concentration (under reduced pressure).The residue producing stands flash chromatography (silica gel;40:1v/v DCM/MeOH to 5:1v/v DCM/ MeOH), to provide product, as faint yellow oil (0.0043g, 29%).LC/MS (2.380 minutes (ES+)),m/z:605.01/ 2[M+2H]+.
Embodiment 4:Determine vitro cytotoxicity
With 150 μ L growth mediums/hole, cell is inoculated enter black-side face clear bottom 96 orifice plate (Costar, ) and putting into 37 DEG C, 5%CO Corning2Incubator before it is allowed in biological cabinet indwelling 1 hour.Second day, prepare 4X The medicine stock solution of concentration, then titrates and is serially diluted for 10 times, thus producing 8 dose point curves, and is added with 50 μ l/ holes Agent, it is repeated twice.Subsequently in 37 DEG C, 5%CO2Lower Incubate cells 48 hours.By with 100 μ L Cell Titer Glo (Promega) solution is incubated 1 hour to measure cytotoxicity, is then come with Fusion HT plate reader (Perkin Elmer) Measurement is luminous.Carry out processing data with Excel (Microsoft) and GraphPad (Prism) to produce dose response curve, then Produce IC50It is worth and collect data.

Claims (33)

1. a kind of compound with Formulas I:
Wherein:
X is NHRN, wherein RNSelected from H and C1-4The group of alkyl composition;
RC1、RC2And RC3Independently selected from H and unsubstituted C1-2Alkyl;
R12Selected from group consisting of:
(ia)C5-10Aryl, optionally substituted by one or more substituent groups, described substituent group is selected from and includes following group:Halogen, nitre Base, cyano group, ether, C1-7Alkyl, C3-7Heterocyclic radical and double-epoxide-C1-3Alkylidene;
(ib)C1-5Radical of saturated aliphatic alkyl;
(ic)C3-6Saturated cyclic alkyls;
(id)Wherein R21、R22And R23It is each independently selected from H, C1-3Saturated alkyl, C2-3Alkenyl, C2-3Alkynyl And cyclopropyl, wherein in R12In group, the sum of carbon atom is not more than 5;
(ie)Wherein R25aAnd R25bOne of be H and another is selected from phenyl, described phenyl is by selected from halogen Base, methyl, methoxyl group group optionally substituted;Pyridine radicals;And thiophenyl;And
(if)Wherein R24It is selected from:H;C1-3Saturated alkyl;C2-3Alkenyl;C2-3Alkynyl;Cyclopropyl;Phenyl, described Phenyl is optionally substituted by the group selected from halogen, methyl, methoxyl group;Pyridine radicals;And thiophenyl;
R6、R6’、R9And R9’It is H;
R7It is C1-4Alkoxyl or OCH2Ph;
(a)R10It is H, and R11It is OH, ORA, wherein RAIt is C1-4Alkyl;Or
(b)R10And R11Form nitrogen-carbon double bond between the nitrogen that they are combined and carbon atom;Or
(c)R10It is H and R11It is SOzM, wherein z are 2 or 3 and M to be univalent medicinal cation;
R " is C3-7Alkylidene;
Y and Y ' is O;
R7’It is selected from and R7Identical group, and R10’And R11’Respectively with R10And R11Identical, if wherein R11And R11’It is SOzM, So M can represent bivalence medicinal cation.
2. compound according to claim 1, wherein, R7Selected from OCH3And OCH2Ph.
3. compound according to claim 1, wherein, RC1、RC2And RC3Independently selected from H and methyl.
4. compound according to claim 3, wherein, RC1、RC2And RC3It is all H.
5. compound according to claim 3, wherein, RC1、RC2And RC3It is all methyl.
6. compound according to any one of claim 1 to 3, wherein, X is NH2.
7. compound according to any one of claim 1 to 3, wherein, R12It is C5-7Aryl.
8. compound according to claim 7, wherein, R12It is phenyl, optionally substituted by one or more substituent groups, described Substituent group is selected from:Halogen, nitro, cyano group, ether, C1-7Alkyl, C3-7Heterocyclic radical and double-epoxide-C1-3Alkylidene.
9. compound according to any one of claim 1 to 3, wherein, R12It is C8-10Aryl, by one or more replacements Base is optionally substituted, and described substituent group is selected from:Halogen, nitro, cyano group, ether, C1-7Alkyl, C3-7Heterocyclic radical and double-epoxide-C1-3Sub- Alkyl.
10. compound according to claim 7, wherein, R12With one to three substituent group.
11. compounds according to claim 7, wherein, R12It is C5-7Aryl, optionally substituted by one or more substituent groups, Described substituent group is selected from methoxyl group, ethyoxyl, fluorine, chlorine, cyano group, double-epoxide-methylene.
12. compounds according to any one of claim 1 to 3, wherein, R12It is C1-5Radical of saturated aliphatic alkyl.
13. compounds according to claim 12, wherein, R12It is methyl, ethyl or propyl group.
14. compounds according to any one of claim 1 to 3, wherein, R12It is C3-6Saturated cyclic alkyls.
15. compounds according to claim 14, wherein, R12It is cyclopropyl.
16. compounds according to any one of claim 1 to 3, wherein, R12It is the group of following formula:
17. compounds according to claim 16, wherein, in R12In group, the sum of carbon atom is not more than 4.
18. compounds according to claim 17, wherein, in R12In group, the sum of carbon atom is not more than 3.
19. compounds according to claim 16, wherein, R21、R22And R23One of be H, and other two groups choosings From H, C1-3Saturated alkyl, C2-3Alkenyl, C2-3Alkynyl and cyclopropyl.
20. compounds according to claim 16, wherein, R21、R22And R23In two be H, and other group choosings From H, C1-3Saturated alkyl, C2-3Alkenyl, C2-3Alkynyl and cyclopropyl.
21. compounds according to any one of claim 1 to 3, wherein, R12It is the group of following formula:
22. compounds according to claim 21, wherein, R12It is following group:
23. compounds according to any one of claim 1 to 3, wherein, R12It is the group of following formula:
24. compounds according to claim 23, wherein, R24Selected from H, methyl, ethyl, vinyl and acetenyl.
25. compounds according to claim 24, wherein, R24Selected from H and methyl.
26. compounds according to any one of claim 1 to 3, wherein, R10And R11Form nitrogen-carbon double bond.
27. compounds according to any one of claim 1 to 3 are used in the medicine treating proliferative disease in preparation Application.
A kind of 28. compounds of Formula II:
Wherein:
RC1、RC2、RC3、X、R6、R7、R9、Y、R”、Y’、R12、R6’、R7’And R9’It is as according in claim 1 to 27 Defined in the compound of the Formulas I described in;
(a)R10It is Troc, and R11It is OTBS;
(b)R10It is SEM and R11It is oxo base;
And R10’And R11’Respectively with R10And R11Identical.
A kind of 29. conjugates with formula III:
L-(LU-D)p(III)
Wherein L is the Fab of antibody or antibody;
LU is formula-A1-L1- connector unit, wherein L1It is dipeptides, selected from val-ala, valine-citrulline and benzene The group of alanine-lysine composition, and A1It is selected from:
Wherein said asterisk represents and L1Junction point, described wavy line represents the junction point with described L, and n is 0 to 6;
Wherein said asterisk represents and L1Junction point, described wavy line represents the junction point with described L, and n is 0 to 6;
Wherein said asterisk represents and L1Junction point, described wavy line represents the junction point with described L, and n is 0 or 1, and m is 0 to 30;Or
Wherein said asterisk represents and L1Junction point, described wavy line represents the junction point with described L, and n is 0 or 1, and m is 0 to 30;
Wherein, with alternatively substituting the group of maleimide derivative selected from following group:C (=O) NH-;- C (=O) O-;- NHC (=O)-;- OC (=O)-;- OC (=O) O-;- NHC (=O) O-;- OC (=O) NH-;- NHC (=O) NH-;- NHC (=O) NH-;- C (=O) NHC (=O)-;-S-;-S-S-;-CH2C (=O)-;- C (=O) CH2-;=N-NH- and-NH-N=;
P is 1 to 20, and
D is drug unit, and described drug unit is the compound according to any one of claim 1 to 27, wherein, LU warp Connected to D by X.
30. conjugates according to claim 29, wherein, A1It is:
Wherein said asterisk represents and L1Junction point, described wavy line represents the junction point with described L, and n is 0 to 6.
31. conjugates according to claim 30, wherein, n is 5.
32. conjugates according to any one of claim 29 to 31 are used for treating proliferative disease in preparation or itself exempts from Application in the medicine of epidemic disease.
A kind of medicine joint of 33. Formula V:
G1-L1-D(V)
Wherein, G1It is selected from:
Wherein said asterisk represents and L1Junction point, and n is 0 to 6;
Wherein said asterisk represents and L1Junction point, and n is 0 to 6;
Wherein said asterisk represents and L1Junction point, n is 0 or 1, and m is 0 to 30;
Wherein said asterisk represents and L1Junction point, n is 0 or 1, and m is 0 to 30;And wherein it is possible to by selected from following Group substitute maleimide base group:- C (=O) OH;-OH;-NH2;-SH;- C (=O) CH2X, wherein X are Cl, Br or I;- CHO;-NHNH2;- C ≡ CH and-N3
L1It is dipeptides, selected from the group of val-ala, valine-citrulline and Phe-Lys composition;
D is the compound according to any one of claim 1 to 27, and wherein X is NHRN, wherein RNSelected from H and C1-4Alkane The group of basis set one-tenth.
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Families Citing this family (113)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0819095D0 (en) 2008-10-17 2008-11-26 Spirogen Ltd Pyrrolobenzodiazepines
CA2795349C (en) 2010-04-15 2016-11-29 Seattle Genetics, Inc. Targeted pyrrolobenzodiazepine conjugates
BR112012026410B8 (en) 2010-04-15 2023-01-31 Spirogen Dev Sarl COMPOUND AND CONJUGATE OF PYROLOBENZODIAZEPINE AND USES THEREOF
SG11201400770SA (en) 2011-09-20 2014-04-28 Spirogen Sarl Pyrrolobenzodiazepines as unsymmetrical dimeric pbd compounds for inclusion in targeted conjugates
EP2751110B1 (en) 2011-10-14 2017-04-19 MedImmune Limited Asymmetrical bis-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-5-one) derivatives for the treatment of proliferative and autoimmune diseases
EP3309162A1 (en) 2011-10-14 2018-04-18 Seattle Genetics, Inc. Targeted conjugates of pyrrolobenzodiazepines
ES2687246T3 (en) 2011-10-14 2018-10-24 Seattle Genetics, Inc. Pyrrolobenzodiazepines and directed conjugates
JP6170497B2 (en) 2011-10-14 2017-07-26 メドイミューン・リミテッドMedImmune Limited Pyrrolobenzodiazepine
EA035405B1 (en) 2012-10-12 2020-06-08 Медимьюн Лимитед Pyrrolobenzodiazepines and conjugates thereof
JP6392765B2 (en) 2012-10-12 2018-09-19 エイディーシー・セラピューティクス・エス・アーAdc Therapeutics Sa Pyrrolobenzodiazepine-antibody conjugate
EP2906249B1 (en) * 2012-10-12 2018-06-27 MedImmune Limited Synthesis and intermediates of pyrrolobenzodiazepine derivatives for conjugation
WO2014057114A1 (en) 2012-10-12 2014-04-17 Adc Therapeutics Sàrl Pyrrolobenzodiazepine-anti-psma antibody conjugates
BR112015008251B1 (en) 2012-10-12 2023-09-26 Medimmune Limited PYRROLOBENZODIAZEPINES, CONJUGATES THEREOF, COMPOSITION AND PHARMACEUTICAL COMPOSITION COMPRISING THE CONJUGATES, USE OF THE CONJUGATES FOR THE TREATMENT OF A PROLIFERATIVE DISEASE AND METHOD FOR PREPARING THE CONJUGATES
DK2906298T3 (en) 2012-10-12 2018-12-17 Adc Therapeutics Sa Pyrrolobenzodiazepine-antibody conjugates
US10751346B2 (en) 2012-10-12 2020-08-25 Medimmune Limited Pyrrolobenzodiazepine—anti-PSMA antibody conjugates
US10695433B2 (en) 2012-10-12 2020-06-30 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
NZ707543A (en) 2012-10-12 2018-09-28 Adc Therapeutics Sa Pyrrolobenzodiazepine-antibody conjugates
EA031585B1 (en) 2012-12-21 2019-01-31 Медимьюн Лимитед Pyrrolobenzodiazepines and conjugates thereof
WO2014096365A1 (en) 2012-12-21 2014-06-26 Spirogen Sàrl Unsymmetrical pyrrolobenzodiazepines-dimers for use in the treatment of proliferative and autoimmune diseases
AU2014229529B2 (en) 2013-03-13 2018-02-15 Medimmune Limited Pyrrolobenzodiazepines and conjugates thereof
SG10201707618TA (en) 2013-03-13 2017-10-30 Seattle Genetics Inc Cyclodextrin and antibody-drug conjugate formulations
EP2968494B1 (en) 2013-03-13 2018-11-14 Seattle Genetics, Inc. Activated carbon filtration for purification of benzodiazepine adcs
JP6445519B2 (en) 2013-03-13 2018-12-26 メドイミューン・リミテッドMedImmune Limited Pyrrolobenzodiazepine and its conjugates
JP6847388B2 (en) 2013-03-15 2021-03-31 レゲネロン ファーマシューティカルス,インコーポレーテッド Bioactive molecules, their conjugates, and therapeutic uses
SG11201601230RA (en) 2013-08-26 2016-03-30 Regeneron Pharma Pharmaceutical compositions comprising macrolide diastereomers, methods of their synthesis and therapeutic uses
CN105873612A (en) * 2013-08-28 2016-08-17 施特姆森特克斯股份有限公司 Engineered anti-DLL3 conjugates and methods of use
SG11201601416VA (en) 2013-08-28 2016-03-30 Stemcentrx Inc Novel sez6 modulators and methods of use
EP3038644B1 (en) 2013-08-28 2021-04-07 AbbVie Stemcentrx LLC Site-specific antibody conjugation methods and compositions
US9950078B2 (en) 2013-10-11 2018-04-24 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
GB201317981D0 (en) 2013-10-11 2013-11-27 Spirogen Sarl Pyrrolobenzodiazepines and conjugates thereof
US10010624B2 (en) 2013-10-11 2018-07-03 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
EP3054986B1 (en) 2013-10-11 2019-03-20 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
GB201317982D0 (en) 2013-10-11 2013-11-27 Spirogen Sarl Pyrrolobenzodiazepines and conjugates thereof
EA201690780A1 (en) 2013-10-15 2016-08-31 Сиэтл Дженетикс, Инк. PEDIATED MEDICINE-LINKS FOR IMPROVED PHARMACOKINETICS OF LJAND-MEDICINE CONJUGATES
CN103641834B (en) * 2013-12-12 2015-12-09 沈阳药科大学 Pyrrolobenzodiazepines * compounds and its preparation method and application
KR102405762B1 (en) * 2013-12-16 2022-06-07 제넨테크, 인크. Peptidomimetic compounds and antibody-drug conjugates thereof
TWI727919B (en) 2013-12-19 2021-05-21 美商西雅圖遺傳學公司 Methylene carbamate linkers for use with targeted-drug conjugates
CR20160437A (en) 2014-02-21 2017-02-20 Abbvie Stemcentrx Llc CONJUGATES OF ANTI-DROSOPHILA ANTIBODIES SIMILAR TO DELTA 3 (ANTI-DLL3) AND MEDICINES FOR USE IN THE TREATMENT AGAINST MELANOMA
AU2015229591B2 (en) 2014-03-11 2020-10-22 Regeneron Pharmaceuticals, Inc. Anti-EGFRvlll antibodies and uses thereof
WO2016037644A1 (en) 2014-09-10 2016-03-17 Medimmune Limited Pyrrolobenzodiazepines and conjugates thereof
GB201416112D0 (en) 2014-09-12 2014-10-29 Medimmune Ltd Pyrrolobenzodiazepines and conjugates thereof
EA201790545A1 (en) 2014-09-12 2017-07-31 Дженентек, Инк. ANTIBODIES AND IMMUNOCONJUGATES AGAINST HER2
EP3223854A1 (en) 2014-11-25 2017-10-04 ADC Therapeutics SA Pyrrolobenzodiazepine-antibody conjugates
EP3245213B1 (en) 2015-01-14 2020-03-04 Bristol-Myers Squibb Company Benzodiazepine dimers, conjugates thereof, and methods of making and using
CN107231804B (en) 2015-01-14 2019-11-26 百时美施贵宝公司 Inferior heteroaryl bridging benzodiazepine * dimer, its conjugate and preparation and application
BR112017020149A8 (en) 2015-03-27 2023-05-02 Regeneron Pharma MAITANSINOID DERIVATIVES, CONJUGATES THEREOF AND METHODS OF USE
GB201506402D0 (en) 2015-04-15 2015-05-27 Berkel Patricius H C Van And Howard Philip W Site-specific antibody-drug conjugates
GB201506411D0 (en) 2015-04-15 2015-05-27 Bergenbio As Humanized anti-axl antibodies
AU2016284340A1 (en) 2015-06-23 2018-02-08 Bristol-Myers Squibb Company Macrocyclic benzodiazepine dimers, conjugates thereof, preparation and uses
SG10202112460VA (en) 2015-07-06 2021-12-30 Regeneron Pharma Multispecific antigen-binding molecules and uses thereof
MA43345A (en) * 2015-10-02 2018-08-08 Hoffmann La Roche PYRROLOBENZODIAZEPINE ANTIBODY-DRUG CONJUGATES AND METHODS OF USE
WO2017096311A1 (en) 2015-12-04 2017-06-08 Seattle Genetics, Inc. Conjugates of quaternized tubulysin compounds
US11793880B2 (en) 2015-12-04 2023-10-24 Seagen Inc. Conjugates of quaternized tubulysin compounds
WO2017100642A1 (en) 2015-12-11 2017-06-15 Regeneron Pharmaceuticals, Inc. Methods for reducing or preventing growth of tumors resistant to egfr and/or erbb3 blockade
CN108779127B (en) 2016-01-25 2022-07-05 里珍纳龙药品有限公司 Maytansinoid derivatives, conjugates thereof, and methods of use
GB201601431D0 (en) 2016-01-26 2016-03-09 Medimmune Ltd Pyrrolobenzodiazepines
GB201602359D0 (en) 2016-02-10 2016-03-23 Medimmune Ltd Pyrrolobenzodiazepine Conjugates
GB201602356D0 (en) 2016-02-10 2016-03-23 Medimmune Ltd Pyrrolobenzodiazepine Conjugates
EP3433278A4 (en) 2016-03-25 2019-11-06 Seattle Genetics, Inc. Process for the preparation of pegylated drug-linkers and intermediates thereof
EP3448891A1 (en) 2016-04-28 2019-03-06 Regeneron Pharmaceuticals, Inc. Methods of making multispecific antigen-binding molecules
GB201607478D0 (en) 2016-04-29 2016-06-15 Medimmune Ltd Pyrrolobenzodiazepine Conjugates
WO2017201132A2 (en) 2016-05-18 2017-11-23 Mersana Therapeutics, Inc. Pyrrolobenzodiazepines and conjugates thereof
JP7049276B2 (en) 2016-06-24 2022-04-06 メルサナ セラピューティクス インコーポレイテッド Pyrrolobenzodiazepines and their conjugates
WO2018002902A1 (en) 2016-07-01 2018-01-04 Glaxosmithkline Intellectual Property (No.2) Limited Antibody-drug conjugates and therapeutic methods using the same
MA46417A (en) 2016-09-23 2019-07-31 Regeneron Pharma ANTI-STEAP2 ANTIBODIES, ANTIBODY-DRUG CONJUGATES, AND BISPECIFIC ANTIGEN-BINDING MOLECULES THAT BIND TO STEAP2 AND CD3, AND THEIR USES
JP7066691B2 (en) 2016-09-23 2022-05-13 リジェネロン・ファーマシューティカルズ・インコーポレイテッド Bispecific anti-MUC16-CD3 antibody and anti-MUC16 drug complex
GB201617466D0 (en) 2016-10-14 2016-11-30 Medimmune Ltd Pyrrolobenzodiazepine conjugates
MX2019005330A (en) 2016-11-08 2019-09-11 Regeneron Pharma Steroids and protein-conjugates thereof.
TWI782930B (en) 2016-11-16 2022-11-11 美商再生元醫藥公司 Anti-met antibodies, bispecific antigen binding molecules that bind met, and methods of use thereof
LT3544636T (en) 2017-02-08 2021-06-25 Adc Therapeutics Sa Pyrrolobenzodiazepine-antibody conjugates
GB201702031D0 (en) 2017-02-08 2017-03-22 Medlmmune Ltd Pyrrolobenzodiazepine-antibody conjugates
US11730822B2 (en) 2017-03-24 2023-08-22 Seagen Inc. Process for the preparation of glucuronide drug-linkers and intermediates thereof
SI3612537T1 (en) 2017-04-18 2022-10-28 Medimmune Limited Pyrrolobenzodiazepine conjugates
CN110536703A (en) 2017-04-20 2019-12-03 Adc治疗有限公司 Use Anti-AXL antibodies-drug conjugate combination treatment
EA201900562A1 (en) 2017-05-18 2020-05-12 Регенерон Фармасьютикалз, Инк. BIS-OCTAGHYDROPHENANTHRENE CARBOXAMIDES AND THEIR PROTEIN CONJUGATES
WO2018213077A1 (en) 2017-05-18 2018-11-22 Regeneron Pharmaceuticals, Inc. Cyclodextrin protein drug conjugates
KR102442736B1 (en) 2017-06-14 2022-09-16 에이디씨 테라퓨틱스 에스에이 Dosage regime for administration of anti-CD19 ADCs
SG11202000358YA (en) 2017-08-18 2020-02-27 Medimmune Ltd Pyrrolobenzodiazepine conjugates
WO2019065964A1 (en) 2017-09-29 2019-04-04 第一三共株式会社 Antibody-pyrrolobenzodiazepine derivative conjugate
MX2020004691A (en) 2017-11-07 2020-08-20 Regeneron Pharma Hydrophilic linkers for antibody drug conjugates.
JP2021502969A (en) 2017-11-14 2021-02-04 メドイミューン・リミテッドMedImmune Limited Pyrrolobenzodiazepine complex
EP3717021A1 (en) 2017-11-27 2020-10-07 Mersana Therapeutics, Inc. Pyrrolobenzodiazepine antibody conjugates
WO2019126691A1 (en) 2017-12-21 2019-06-27 Mersana Therapeutics, Inc. Pyrrolobenzodiazepine antibody conjugates
CN112004557A (en) 2018-01-08 2020-11-27 里珍纳龙药品有限公司 Steroid compounds and antibody conjugates thereof
GB201803342D0 (en) 2018-03-01 2018-04-18 Medimmune Ltd Methods
GB201806022D0 (en) 2018-04-12 2018-05-30 Medimmune Ltd Pyrrolobenzodiazepines and conjugates thereof
AU2019262953A1 (en) 2018-04-30 2020-11-19 Regeneron Pharmaceuticals, Inc. Antibodies, and bispecific antigen-binding molecules that bind HER2 and/or APLP2, conjugates, and uses thereof
AU2019265703A1 (en) 2018-05-09 2020-11-19 Regeneron Pharmaceuticals, Inc. Anti-MSR1 antibodies and methods of use thereof
EP3793591A1 (en) 2018-05-17 2021-03-24 Regeneron Pharmaceuticals, Inc. Anti-cd63 antibodies, conjugates, and uses thereof
JP2021525730A (en) * 2018-05-29 2021-09-27 イントゥーセル,インコーポレーティッド New benzodiazepine derivatives and their use
EA202191430A1 (en) 2018-11-20 2021-11-29 Регенерон Фармасьютикалз, Инк. BIS-OCTAHYDROPHENANTHENETRENE CARBOXAMIDE DERIVATIVES AND THEIR PROTEIN CONJUGATES
JP2022516427A (en) 2018-12-21 2022-02-28 レゲネロン ファーマシューティカルス,インコーポレーテッド Tubricin and Protein-Tubricin Conjugate
MA54545A (en) 2018-12-21 2021-10-27 Regeneron Pharma RIFAMYCIN ANALOGS AND ANTIBODY-DRUG CONJUGATE THEREOF
CA3125998A1 (en) 2019-01-08 2020-07-16 Regeneron Pharmaceuticals, Inc. Traceless linkers and protein-conjugates thereof
JP2022523360A (en) 2019-02-21 2022-04-22 リジェネロン・ファーマシューティカルズ・インコーポレイテッド A method for treating eye cancer using an anti-MET antibody that binds to MET and a bispecific antigen-binding molecule.
CN110078749B (en) * 2019-06-04 2021-01-01 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) 3a, 3a' -difuran [2,3-b ] indoline compound, preparation method, pharmaceutical composition and application
CA3146933A1 (en) 2019-09-16 2021-03-25 Marcus KELLY Radiolabeled met binding proteins for immuno-pet imaging
US11814428B2 (en) 2019-09-19 2023-11-14 Regeneron Pharmaceuticals, Inc. Anti-PTCRA antibody-drug conjugates and uses thereof
WO2021080608A1 (en) 2019-10-25 2021-04-29 Medimmune, Llc Branched moiety for use in conjugates
KR20210086557A (en) 2019-12-31 2021-07-08 주식회사 레고켐 바이오사이언스 Pyrrolobenzodiazepine derivatives and its ligand-linker conjugate
AU2021210987A1 (en) 2020-01-24 2022-08-04 Regeneron Pharmaceuticals, Inc. Protein-antiviral compound conjugates
CN115175737A (en) 2020-02-28 2022-10-11 瑞泽恩制药公司 Bispecific antigen binding molecules that bind HER2 and methods of use thereof
US11701427B2 (en) 2020-04-16 2023-07-18 Regeneron Pharmaceuticals, Inc. Diels-alder conjugation methods
BR112022024361A2 (en) 2020-06-24 2022-12-27 Regeneron Pharma TUBULISINS AND PROTEIN-TUBULISIN CONJUGATES
EP4178625A1 (en) 2020-07-13 2023-05-17 Regeneron Pharmaceuticals, Inc. Camptothecin analogs conjugated to a glutamine residue in a protein, and their use
CA3191304A1 (en) 2020-09-14 2022-03-17 Amy Han Antibody-drug conjugates comprising glp1 peptidomimetics and uses thereof
WO2022087243A1 (en) 2020-10-22 2022-04-28 Regeneron Pharmaceuticals, Inc. Anti-fgfr2 antibodies and methods of use thereof
CA3220081A1 (en) 2021-07-28 2023-02-02 Thomas Nittoli Protein-antiviral compound conjugates
US20230414775A1 (en) 2021-12-29 2023-12-28 Regeneron Pharmaceuticals, Inc. Tubulysins and protein-tubulysin conjugates
US20230287138A1 (en) 2022-01-12 2023-09-14 Regneron Pharmaceuticals, Inc. Protein-drug conjugates comprising camptothecin analogs and methods of use thereof
WO2023137443A1 (en) 2022-01-14 2023-07-20 Regeneron Pharmaceuticals, Inc. Verrucarin a derivatives and antibody drug conjugates thereof
WO2023173132A1 (en) 2022-03-11 2023-09-14 Regeneron Pharmaceuticals, Inc. Anti-glp1r antibody-drug conjugates comprising glp1 peptidomimetics and uses thereof
WO2024020164A2 (en) 2022-07-21 2024-01-25 Firefly Bio, Inc. Glucocorticoid receptor agonists and conjugates thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000012508A2 (en) * 1998-08-27 2000-03-09 Spirogen Limited Pyrrolbenzodiazepines
WO2005085251A1 (en) * 2004-03-01 2005-09-15 Spirogen Limited 11-hydroxy-5h-pyrrolo[2,1-c][1,4]benzodiazepin-5-one derivatives as key intermediates for the preparation of c2 substituted pyrrolobenzodiazepines
CN1735616A (en) * 2002-11-14 2006-02-15 斯皮罗根有限公司 Pyrrolobenzodiazepines
CN101171257A (en) * 2005-04-21 2008-04-30 斯皮罗根有限公司 Pyrrolobenzodiazepines compound
WO2010043880A1 (en) * 2008-10-17 2010-04-22 Spirogen Limited Unsymmetrical pyrrolobenzodiazepine-dimers for treatment of proliferative diseases

Family Cites Families (114)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3361742A (en) 1964-12-07 1968-01-02 Hoffmann La Roche 5-oxo-1h-pyrrolo-[2, 1-c][1, 4]-benzodiazepin-2-crylamides
US3523941A (en) 1967-03-06 1970-08-11 Hoffmann La Roche Benzodiazepine compounds and process for their preparation
US3524849A (en) 1967-10-27 1970-08-18 Hoffmann La Roche Process for the preparation of pyrrolo-benzodiazepine acrylamides and intermediates useful therein
JPS4843755B1 (en) 1969-06-26 1973-12-20
IL33558A (en) 1968-12-30 1973-10-25 Fujisawa Pharmaceutical Co Antibiotic pyrrolo-benzodiazepine compound,its derivatives and processes for their production
FR2027356A1 (en) 1968-12-30 1970-09-25 Fujisawa Pharmaceutical Co Benzodiazepinone antibiotics
JPS5382792U (en) 1976-12-10 1978-07-08
JPS585916B2 (en) 1977-12-27 1983-02-02 株式会社ミドリ十字 New benzodiazepine compounds
JPS5615289A (en) 1979-07-17 1981-02-14 Green Cross Corp:The Novel benzodiazepinnbased compound 3
JPH0353356Y2 (en) 1981-02-06 1991-11-21
CA1173441A (en) 1981-02-27 1984-08-28 Hoffmann-La Roche Limited Imidazodiazepines
CA1184175A (en) 1981-02-27 1985-03-19 Walter Hunkeler Imidazodiazepines
CA1185602A (en) 1981-02-27 1985-04-16 Emilio Kyburz Imidazodiazepines
JPS58180487A (en) 1982-04-16 1983-10-21 Kyowa Hakko Kogyo Co Ltd Antibiotic dc-81 and its preparation
JPS58180487U (en) 1982-05-28 1983-12-02 松下電工株式会社 Light beam alarm assembly
US4427588A (en) 1982-11-08 1984-01-24 Bristol-Myers Company Process for conversion of oxotomaymycin to tomaymycin
US4427587A (en) 1982-11-10 1984-01-24 Bristol-Myers Company Total synthesis of antitumor antibiotics BBM-2040A and BBM-2040B
JPS59152329A (en) 1983-02-17 1984-08-31 Green Cross Corp:The Local disorder inhibitor
JPS59190992A (en) * 1983-04-12 1984-10-29 Green Cross Corp:The Benzodiazepine derivative
FR2586683B1 (en) 1985-08-29 1988-07-01 Centre Nat Rech Scient NOVEL NEOTHRAMYCIN DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS
JP2660201B2 (en) 1988-08-05 1997-10-08 塩野義製薬株式会社 Novel pyrrolo [1,4] benzodiazepine derivatives and senile dementia drugs
FR2676230B1 (en) 1991-05-07 1993-08-27 Centre Nat Rech Scient NOVEL PYRROLO [1,4] -BENZODIAZEPINES DERIVATIVES, PROCESS FOR THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM.
GB9205051D0 (en) 1992-03-09 1992-04-22 Cancer Res Campaign Tech Pyrrolobenzodiazepine derivatives,their preparation,and compositions containing them
FR2696176B1 (en) 1992-09-28 1994-11-10 Synthelabo Piperidine derivatives, their preparation and their therapeutic application.
US6214345B1 (en) 1993-05-14 2001-04-10 Bristol-Myers Squibb Co. Lysosomal enzyme-cleavable antitumor drug conjugates
GB9316162D0 (en) 1993-08-04 1993-09-22 Zeneca Ltd Fungicides
ATE276536T1 (en) 1998-07-08 2004-10-15 E Ink Corp METHOD FOR IMPROVING COLOR RENDERING IN ELECTROPHORETIC DEVICES USING MICROCAPSULES
GB9818731D0 (en) 1998-08-27 1998-10-21 Univ Portsmouth Compounds
GB9818732D0 (en) 1998-08-27 1998-10-21 Univ Portsmouth Collection of compounds
GB9818730D0 (en) 1998-08-27 1998-10-21 Univ Portsmouth Collections of compounds
US6909006B1 (en) 1999-08-27 2005-06-21 Spirogen Limited Cyclopropylindole derivatives
ES2254492T3 (en) 2000-09-19 2006-06-16 Moses Lee COMPOSITIONS AND PROCEDURES FOR THE USE OF AQUIRAL ANALOGS OF CC-1065 AND DUOCARMYCINES.
US6362331B1 (en) 2001-03-30 2002-03-26 Council Of Scientific And Industrial Research Process for the preparation of antitumor agents
US6660856B2 (en) 2002-03-08 2003-12-09 Kaohsiung Medical University Synthesis of pyrrolo[2,1-c][1,4]benzodiazepine analogues
CA2802205C (en) 2002-07-31 2016-01-19 Seattle Genetics, Inc. Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease
US20040138269A1 (en) 2002-10-11 2004-07-15 Sugen, Inc. Substituted pyrroles as kinase inhibitors
ATE421967T1 (en) 2003-03-31 2009-02-15 Council Scient Ind Res NON-CROSS-LINKING PYRROLOÄ2,1-CÜÄ1, 4ÜBENZODIAZEPINES AS POTENTIAL ANTITUMOR AGENTS AND THEIR PRODUCTION
GB0321295D0 (en) 2003-09-11 2003-10-15 Spirogen Ltd Synthesis of protected pyrrolobenzodiazepines
GB0416511D0 (en) 2003-10-22 2004-08-25 Spirogen Ltd Pyrrolobenzodiazepines
WO2005040170A2 (en) 2003-10-22 2005-05-06 Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Pyrrolobenzodiazepine derivatives, compositions comprising the same and methods related thereto
KR101438983B1 (en) 2003-11-06 2014-09-05 시애틀 지네틱스, 인크. Monomethylvaline compounds capable of conjugation to ligands
JP5064037B2 (en) 2004-02-23 2012-10-31 ジェネンテック, インコーポレイテッド Heterocyclic self-destructive linkers and conjugates
GB0404577D0 (en) 2004-03-01 2004-04-07 Spirogen Ltd Pyrrolobenzodiazepines
GB0404574D0 (en) 2004-03-01 2004-04-07 Spirogen Ltd Amino acids
GB0404578D0 (en) 2004-03-01 2004-04-07 Spirogen Ltd Pyrrolobenzodiazepines
DE102004010943A1 (en) 2004-03-03 2005-09-29 Degussa Ag Process for the preparation of N-protected 4-ketproline derivatives
JP5166861B2 (en) 2004-03-09 2013-03-21 スピロゲン リミティッド Pyrrolobenzodiazepine
FR2869231B1 (en) 2004-04-27 2008-03-14 Sod Conseils Rech Applic THERAPEUTIC COMPOSITION CONTAINING AT LEAST ONE PYRROLOBENZODIAZEPINE DERIVATIVE AND FLUDARABINE
GB0410725D0 (en) 2004-05-13 2004-06-16 Spirogen Ltd Pyrrolobenzodiazepine therapeutic agents
RU2412947C2 (en) 2004-09-23 2011-02-27 Дженентек, Инк. Antibodies, constructed on cysteine basis and their conjugates
JP2006203186A (en) 2004-12-24 2006-08-03 Showa Denko Kk Method of producing thermoelectric semiconductor alloy, thermoelectric conversion module, and thermoelectric power generation device
EP2511299A1 (en) 2005-04-19 2012-10-17 Seattle Genetics, Inc. Humanized anti-CD70 binding agents and uses thereof
KR101396095B1 (en) 2005-04-21 2014-05-15 스피로즌 살 Pyrrolobenzodiazepines
EP1931671B1 (en) 2005-10-05 2009-04-08 Spirogen Limited Alkyl 4- [4- (5-oxo-2, 3, 5, 11a-tetrahyd0-5h-pyrr0l0 [2, 1-c][1, 4]benzodiazepine-8-yloxy) -butyrylamino]-1h-pyrrole-2-carboxylate derivatives and related compounds for the treatment of a proliferative disease
US20070154906A1 (en) 2005-10-05 2007-07-05 Spirogen Ltd. Methods to identify therapeutic candidates
DK1813614T3 (en) 2006-01-25 2012-01-23 Sanofi Sa Cytotoxic agents comprising novel tomaymycin derivatives
ZA200900545B (en) 2006-07-18 2010-03-31 Sanofi Aventis Antagonist antibody against EPHA2 for the treatment of cancer
EP1914242A1 (en) 2006-10-19 2008-04-23 Sanofi-Aventis Novel anti-CD38 antibodies for the treatment of cancer
WO2008050140A2 (en) 2006-10-27 2008-05-02 Spirogen Limited Compounds for treatment of parasitic infection
EP2099823B2 (en) 2006-12-01 2022-02-09 Seagen Inc. Variant target binding agents and uses thereof
WO2009011753A2 (en) 2007-07-11 2009-01-22 The Regents Of The University Of California Nanostructured polymer membranes for proton conduction
DK2019104T3 (en) 2007-07-19 2013-12-16 Sanofi Sa Cytotoxic agents comprising novel tomaymycin derivatives and therapeutic use thereof
GB0722088D0 (en) 2007-11-09 2007-12-19 Spirogen Ltd Pyrrolobenzodiazepines
GB0722087D0 (en) 2007-11-09 2007-12-19 Spirogen Ltd Polyamides
US8750407B2 (en) 2008-06-17 2014-06-10 Telefonaktiebolaget L M Ericsson (Publ) Transmitter and method for transmitting soft pilot symbols in a digital communication system
GB0813432D0 (en) 2008-07-22 2008-08-27 Spirogen Ltd Pyrrolobenzodiazepines
GB0819097D0 (en) 2008-10-17 2008-11-26 Spirogen Ltd Pyrrolobenzodiazepines
KR101835033B1 (en) 2009-02-05 2018-03-08 이뮤노젠 아이엔씨 Novel benzodiazepine derivatives
FR2949469A1 (en) 2009-08-25 2011-03-04 Sanofi Aventis ANTICANCER DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
CA2775350A1 (en) 2009-09-24 2011-03-31 Seattle Genetics, Inc. Dr5 ligand drug conjugates
EP2534158B1 (en) 2010-02-09 2014-01-08 Bristol-Myers Squibb Company Benzylpyrrolidinone derivatives as modulators of chemokine receptor activity
BR112012026410B8 (en) 2010-04-15 2023-01-31 Spirogen Dev Sarl COMPOUND AND CONJUGATE OF PYROLOBENZODIAZEPINE AND USES THEREOF
CA2795349C (en) 2010-04-15 2016-11-29 Seattle Genetics, Inc. Targeted pyrrolobenzodiazepine conjugates
JP5972864B2 (en) 2010-04-15 2016-08-17 メディミューン リミテッド Pyrrolobenzodiazepines and their conjugates
GB201006340D0 (en) 2010-04-15 2010-06-02 Spirogen Ltd Synthesis method and intermediates
CN107335061B (en) 2011-02-15 2021-09-07 伊缪诺金公司 Cytotoxic benzodiazepine derivatives
SG11201400770SA (en) 2011-09-20 2014-04-28 Spirogen Sarl Pyrrolobenzodiazepines as unsymmetrical dimeric pbd compounds for inclusion in targeted conjugates
JP6170497B2 (en) 2011-10-14 2017-07-26 メドイミューン・リミテッドMedImmune Limited Pyrrolobenzodiazepine
EP2751110B1 (en) 2011-10-14 2017-04-19 MedImmune Limited Asymmetrical bis-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-5-one) derivatives for the treatment of proliferative and autoimmune diseases
ES2687246T3 (en) 2011-10-14 2018-10-24 Seattle Genetics, Inc. Pyrrolobenzodiazepines and directed conjugates
MX350152B (en) 2011-10-14 2017-08-29 Medimmune Ltd Pyrrolobenzodiazepines and conjugates thereof.
EP3309162A1 (en) 2011-10-14 2018-04-18 Seattle Genetics, Inc. Targeted conjugates of pyrrolobenzodiazepines
CN104011018B (en) 2011-10-14 2016-12-14 麦迪穆有限责任公司 Can be used for preparing the tall and erect synthetic method of Pyrrolobenzodiazepines and intermediate
CA2872205C (en) 2012-04-30 2020-07-21 Ucl Business Plc Pyrrolobenzodiazepines
KR101960129B1 (en) 2012-04-30 2019-03-19 메디뮨 리미티드 Pyrrolobenzodiazepines
WO2014011518A1 (en) 2012-07-09 2014-01-16 Genentech, Inc. Immunoconjugates comprising anti-cd22 antibodies
WO2014011519A1 (en) 2012-07-09 2014-01-16 Genentech, Inc. Immunoconjugates comprising anti-cd79b antibodies
AR091961A1 (en) 2012-08-02 2015-03-11 Genentech Inc IMMUNOCONJUGADOS AND ANTI-ETBR ANTIBODIES (ENDOTHELINE B RECEIVER)
US10695433B2 (en) 2012-10-12 2020-06-30 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
US10751346B2 (en) 2012-10-12 2020-08-25 Medimmune Limited Pyrrolobenzodiazepine—anti-PSMA antibody conjugates
EP2906252B1 (en) 2012-10-12 2017-06-14 ADC Therapeutics SA Pyrrolobenzodiazepine-anti-her2 antibody conjugates
DK2906298T3 (en) 2012-10-12 2018-12-17 Adc Therapeutics Sa Pyrrolobenzodiazepine-antibody conjugates
EP2906249B1 (en) 2012-10-12 2018-06-27 MedImmune Limited Synthesis and intermediates of pyrrolobenzodiazepine derivatives for conjugation
NZ707543A (en) 2012-10-12 2018-09-28 Adc Therapeutics Sa Pyrrolobenzodiazepine-antibody conjugates
WO2014057114A1 (en) 2012-10-12 2014-04-17 Adc Therapeutics Sàrl Pyrrolobenzodiazepine-anti-psma antibody conjugates
JP6392765B2 (en) 2012-10-12 2018-09-19 エイディーシー・セラピューティクス・エス・アーAdc Therapeutics Sa Pyrrolobenzodiazepine-antibody conjugate
BR112015008251B1 (en) 2012-10-12 2023-09-26 Medimmune Limited PYRROLOBENZODIAZEPINES, CONJUGATES THEREOF, COMPOSITION AND PHARMACEUTICAL COMPOSITION COMPRISING THE CONJUGATES, USE OF THE CONJUGATES FOR THE TREATMENT OF A PROLIFERATIVE DISEASE AND METHOD FOR PREPARING THE CONJUGATES
EA035405B1 (en) 2012-10-12 2020-06-08 Медимьюн Лимитед Pyrrolobenzodiazepines and conjugates thereof
WO2014057118A1 (en) 2012-10-12 2014-04-17 Adc Therapeutics Sarl Pyrrolobenzodiazepine-anti-cd22 antibody conjugates
WO2014096365A1 (en) 2012-12-21 2014-06-26 Spirogen Sàrl Unsymmetrical pyrrolobenzodiazepines-dimers for use in the treatment of proliferative and autoimmune diseases
EA031585B1 (en) 2012-12-21 2019-01-31 Медимьюн Лимитед Pyrrolobenzodiazepines and conjugates thereof
WO2014130879A2 (en) 2013-02-22 2014-08-28 Stem Centrx, Inc. Novel antibody conjugates and uses thereof
BR112015023333A8 (en) 2013-03-13 2018-04-17 Medimmune Ltd pyrrolbenzodiazepines and conjugates thereof
AU2014229529B2 (en) 2013-03-13 2018-02-15 Medimmune Limited Pyrrolobenzodiazepines and conjugates thereof
JP6445519B2 (en) 2013-03-13 2018-12-26 メドイミューン・リミテッドMedImmune Limited Pyrrolobenzodiazepine and its conjugates
WO2014174111A1 (en) 2013-04-26 2014-10-30 Pierre Fabre Medicament Axl antibody-drug conjugate and its use for the treatment of cancer
EP3054986B1 (en) 2013-10-11 2019-03-20 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
GB201317981D0 (en) 2013-10-11 2013-11-27 Spirogen Sarl Pyrrolobenzodiazepines and conjugates thereof
EP3054984A1 (en) 2013-10-11 2016-08-17 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
US9950078B2 (en) 2013-10-11 2018-04-24 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
GB201317982D0 (en) 2013-10-11 2013-11-27 Spirogen Sarl Pyrrolobenzodiazepines and conjugates thereof
US10010624B2 (en) 2013-10-11 2018-07-03 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
KR102405762B1 (en) 2013-12-16 2022-06-07 제넨테크, 인크. Peptidomimetic compounds and antibody-drug conjugates thereof
GB201406767D0 (en) 2014-04-15 2014-05-28 Cancer Rec Tech Ltd Humanized anti-Tn-MUC1 antibodies anf their conjugates

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000012508A2 (en) * 1998-08-27 2000-03-09 Spirogen Limited Pyrrolbenzodiazepines
CN1735616A (en) * 2002-11-14 2006-02-15 斯皮罗根有限公司 Pyrrolobenzodiazepines
WO2005085251A1 (en) * 2004-03-01 2005-09-15 Spirogen Limited 11-hydroxy-5h-pyrrolo[2,1-c][1,4]benzodiazepin-5-one derivatives as key intermediates for the preparation of c2 substituted pyrrolobenzodiazepines
CN101171257A (en) * 2005-04-21 2008-04-30 斯皮罗根有限公司 Pyrrolobenzodiazepines compound
WO2010043880A1 (en) * 2008-10-17 2010-04-22 Spirogen Limited Unsymmetrical pyrrolobenzodiazepine-dimers for treatment of proliferative diseases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Design, synthesis, and in vitro evaluation of dipeptide-based antibody minor groove binder conjugates;Scott C. Jeffrey等;《J.Med.Chem》;20051231;第48卷(第5期);第1344-1358页 *

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